WO2000074634A2 - Methods and compositions for modulating cell proliferation and cell death - Google Patents
Methods and compositions for modulating cell proliferation and cell death Download PDFInfo
- Publication number
- WO2000074634A2 WO2000074634A2 PCT/US2000/040103 US0040103W WO0074634A2 WO 2000074634 A2 WO2000074634 A2 WO 2000074634A2 US 0040103 W US0040103 W US 0040103W WO 0074634 A2 WO0074634 A2 WO 0074634A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fgf
- cell
- cytotoxic agent
- tumor
- subject
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 115
- 230000030833 cell death Effects 0.000 title claims description 20
- 239000000203 mixture Substances 0.000 title abstract description 7
- 230000004663 cell proliferation Effects 0.000 title description 4
- 101150021185 FGF gene Proteins 0.000 claims abstract description 264
- 239000002254 cytotoxic agent Substances 0.000 claims abstract description 214
- 229940127089 cytotoxic agent Drugs 0.000 claims abstract description 214
- 231100000599 cytotoxic agent Toxicity 0.000 claims abstract description 214
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 71
- 230000005855 radiation Effects 0.000 claims abstract description 53
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 47
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 45
- 102000003390 tumor necrosis factor Human genes 0.000 claims abstract description 45
- 239000000556 agonist Substances 0.000 claims abstract description 42
- 239000003112 inhibitor Substances 0.000 claims abstract description 25
- 102000015696 Interleukins Human genes 0.000 claims abstract description 24
- 108010063738 Interleukins Proteins 0.000 claims abstract description 24
- 229940044684 anti-microtubule agent Drugs 0.000 claims abstract description 23
- 230000002452 interceptive effect Effects 0.000 claims abstract description 23
- 230000019491 signal transduction Effects 0.000 claims abstract description 23
- 102000014150 Interferons Human genes 0.000 claims abstract description 20
- 108010050904 Interferons Proteins 0.000 claims abstract description 20
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 claims abstract description 19
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 claims abstract description 19
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 claims abstract description 19
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 claims abstract description 19
- 229940100198 alkylating agent Drugs 0.000 claims abstract description 19
- 239000002168 alkylating agent Substances 0.000 claims abstract description 19
- 239000000138 intercalating agent Substances 0.000 claims abstract description 19
- 229940079322 interferon Drugs 0.000 claims abstract description 19
- 230000000340 anti-metabolite Effects 0.000 claims abstract description 17
- 229940100197 antimetabolite Drugs 0.000 claims abstract description 17
- 239000002256 antimetabolite Substances 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 17
- 230000002147 killing effect Effects 0.000 claims abstract description 11
- 230000006378 damage Effects 0.000 claims abstract description 9
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 9
- 206010028851 Necrosis Diseases 0.000 claims abstract description 6
- 230000006907 apoptotic process Effects 0.000 claims abstract description 6
- 230000017074 necrotic cell death Effects 0.000 claims abstract description 6
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 5
- 208000032839 leukemia Diseases 0.000 claims abstract description 5
- 230000003211 malignant effect Effects 0.000 claims abstract description 3
- -1 UFT Chemical compound 0.000 claims description 184
- 239000005557 antagonist Substances 0.000 claims description 143
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 88
- 108010000817 Leuprolide Proteins 0.000 claims description 84
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 84
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 79
- 229960005314 suramin Drugs 0.000 claims description 78
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 claims description 78
- 210000004027 cell Anatomy 0.000 claims description 77
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 72
- 108010069236 Goserelin Proteins 0.000 claims description 72
- 229930012538 Paclitaxel Natural products 0.000 claims description 49
- 229960001592 paclitaxel Drugs 0.000 claims description 49
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 49
- 229940063683 taxotere Drugs 0.000 claims description 47
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 46
- 229960004125 ketoconazole Drugs 0.000 claims description 46
- 229960004679 doxorubicin Drugs 0.000 claims description 44
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 43
- 229960002074 flutamide Drugs 0.000 claims description 43
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 43
- 229960005277 gemcitabine Drugs 0.000 claims description 43
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 claims description 43
- 229940087857 lupron Drugs 0.000 claims description 43
- 229960002913 goserelin Drugs 0.000 claims description 42
- 229960001603 tamoxifen Drugs 0.000 claims description 42
- 229960004562 carboplatin Drugs 0.000 claims description 41
- 190000008236 carboplatin Chemical compound 0.000 claims description 41
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 41
- 229960004338 leuprorelin Drugs 0.000 claims description 41
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 39
- 229960004316 cisplatin Drugs 0.000 claims description 39
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 39
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 38
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 38
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 38
- 229960001904 epirubicin Drugs 0.000 claims description 38
- 229960002949 fluorouracil Drugs 0.000 claims description 38
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 36
- 102000006992 Interferon-alpha Human genes 0.000 claims description 33
- 108010047761 Interferon-alpha Proteins 0.000 claims description 33
- 230000036470 plasma concentration Effects 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 208000035475 disorder Diseases 0.000 claims description 28
- 201000011510 cancer Diseases 0.000 claims description 26
- 210000004881 tumor cell Anatomy 0.000 claims description 26
- 230000035755 proliferation Effects 0.000 claims description 22
- 229940121849 Mitotic inhibitor Drugs 0.000 claims description 21
- 210000001519 tissue Anatomy 0.000 claims description 20
- 241000282414 Homo sapiens Species 0.000 claims description 19
- 229960004768 irinotecan Drugs 0.000 claims description 17
- 108090000623 proteins and genes Proteins 0.000 claims description 17
- 230000012010 growth Effects 0.000 claims description 14
- 239000012634 fragment Substances 0.000 claims description 13
- 229960000390 fludarabine Drugs 0.000 claims description 11
- 102000005962 receptors Human genes 0.000 claims description 11
- 108020003175 receptors Proteins 0.000 claims description 11
- 108091008794 FGF receptors Proteins 0.000 claims description 10
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 claims description 10
- 230000002062 proliferating effect Effects 0.000 claims description 9
- 230000025084 cell cycle arrest Effects 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 230000000968 intestinal effect Effects 0.000 claims description 8
- 208000003154 papilloma Diseases 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 238000002512 chemotherapy Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000003200 Adenoma Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 230000007423 decrease Effects 0.000 claims description 5
- 230000017095 negative regulation of cell growth Effects 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 229920002971 Heparan sulfate Polymers 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 4
- 102000036639 antigens Human genes 0.000 claims description 4
- 108091007433 antigens Proteins 0.000 claims description 4
- 210000000481 breast Anatomy 0.000 claims description 4
- 230000022534 cell killing Effects 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims description 4
- 229960002897 heparin Drugs 0.000 claims description 4
- 229920000669 heparin Polymers 0.000 claims description 4
- 239000003055 low molecular weight heparin Substances 0.000 claims description 4
- 229940127215 low-molecular weight heparin Drugs 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 210000000214 mouth Anatomy 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 210000003491 skin Anatomy 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 208000009956 adenocarcinoma Diseases 0.000 claims description 3
- 230000001919 adrenal effect Effects 0.000 claims description 3
- 210000003679 cervix uteri Anatomy 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 210000000442 hair follicle cell Anatomy 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 201000005296 lung carcinoma Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 210000003800 pharynx Anatomy 0.000 claims description 3
- 238000007910 systemic administration Methods 0.000 claims description 3
- 208000002845 Adenomyoepithelioma Diseases 0.000 claims description 2
- 201000003076 Angiosarcoma Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000023328 Basedow disease Diseases 0.000 claims description 2
- 206010061000 Benign pancreatic neoplasm Diseases 0.000 claims description 2
- 206010004593 Bile duct cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010062564 Cementoblastoma Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 201000005262 Chondroma Diseases 0.000 claims description 2
- 208000010126 Chondromatosis Diseases 0.000 claims description 2
- 208000019591 Chondromyxoid fibroma Diseases 0.000 claims description 2
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 2
- 201000009047 Chordoma Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 206010048832 Colon adenoma Diseases 0.000 claims description 2
- 208000035984 Colonic Polyps Diseases 0.000 claims description 2
- 208000009798 Craniopharyngioma Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 201000009051 Embryonal Carcinoma Diseases 0.000 claims description 2
- 206010014967 Ependymoma Diseases 0.000 claims description 2
- 208000003021 Erythroplasia Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 2
- 208000007659 Fibroadenoma Diseases 0.000 claims description 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010060850 Gastric adenoma Diseases 0.000 claims description 2
- 206010017817 Gastric polyps Diseases 0.000 claims description 2
- 206010018498 Goitre Diseases 0.000 claims description 2
- 206010018691 Granuloma Diseases 0.000 claims description 2
- 208000015023 Graves' disease Diseases 0.000 claims description 2
- 208000002927 Hamartoma Diseases 0.000 claims description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 claims description 2
- 206010019629 Hepatic adenoma Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 2
- 206010024612 Lipoma Diseases 0.000 claims description 2
- 208000013836 Malacoplakia Diseases 0.000 claims description 2
- 208000007054 Medullary Carcinoma Diseases 0.000 claims description 2
- 208000000172 Medulloblastoma Diseases 0.000 claims description 2
- 206010027145 Melanocytic naevus Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 208000005927 Myosarcoma Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000007256 Nevus Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 201000010133 Oligodendroglioma Diseases 0.000 claims description 2
- 206010048757 Oncocytoma Diseases 0.000 claims description 2
- 206010068322 Oral papilloma Diseases 0.000 claims description 2
- 208000001715 Osteoblastoma Diseases 0.000 claims description 2
- 208000002063 Oxyphilic Adenoma Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000007641 Pinealoma Diseases 0.000 claims description 2
- 208000037062 Polyps Diseases 0.000 claims description 2
- 206010051807 Pseudosarcoma Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 208000014070 Vestibular schwannoma Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- 208000004064 acoustic neuroma Diseases 0.000 claims description 2
- 208000031112 adenoma of pancreas Diseases 0.000 claims description 2
- 208000025768 adenoma of small intestine Diseases 0.000 claims description 2
- 206010001323 adrenal adenoma Diseases 0.000 claims description 2
- 208000015234 adrenal cortex adenoma Diseases 0.000 claims description 2
- 201000010110 axial osteomalacia Diseases 0.000 claims description 2
- 206010004300 benign neoplasm of adrenal gland Diseases 0.000 claims description 2
- 201000007180 bile duct carcinoma Diseases 0.000 claims description 2
- 208000014117 bile duct papillary neoplasm Diseases 0.000 claims description 2
- 201000000790 biliary papillomatosis Diseases 0.000 claims description 2
- 201000001531 bladder carcinoma Diseases 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 208000011803 breast fibrocystic disease Diseases 0.000 claims description 2
- 201000002209 breast lipoma Diseases 0.000 claims description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 201000005217 chondroblastoma Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000031513 cyst Diseases 0.000 claims description 2
- 208000002445 cystadenocarcinoma Diseases 0.000 claims description 2
- 230000002124 endocrine Effects 0.000 claims description 2
- 208000016018 endometrial polyp Diseases 0.000 claims description 2
- 208000037828 epithelial carcinoma Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 201000010103 fibrous dysplasia Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000001838 giant cell reparative granuloma Diseases 0.000 claims description 2
- 201000003872 goiter Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000002222 hemangioblastoma Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 208000024596 kidney oncocytoma Diseases 0.000 claims description 2
- 206010024627 liposarcoma Diseases 0.000 claims description 2
- 208000037829 lymphangioendotheliosarcoma Diseases 0.000 claims description 2
- 208000012804 lymphangiosarcoma Diseases 0.000 claims description 2
- 208000010560 malakoplakia Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 2
- 206010027191 meningioma Diseases 0.000 claims description 2
- 201000002077 muscle cancer Diseases 0.000 claims description 2
- 208000007538 neurilemmoma Diseases 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 208000003388 osteoid osteoma Diseases 0.000 claims description 2
- 208000008798 osteoma Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 208000025661 ovarian cyst Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 208000004019 papillary adenocarcinoma Diseases 0.000 claims description 2
- 201000010198 papillary carcinoma Diseases 0.000 claims description 2
- 210000003899 penis Anatomy 0.000 claims description 2
- 208000024724 pineal body neoplasm Diseases 0.000 claims description 2
- 201000004123 pineal gland cancer Diseases 0.000 claims description 2
- 208000023110 primary bone dysplasia with increased bone density Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 208000005039 renal oncocytoma Diseases 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 201000008662 sclerosing adenosis of breast Diseases 0.000 claims description 2
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 206010042863 synovial sarcoma Diseases 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 206010046811 uterine polyp Diseases 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 210000003905 vulva Anatomy 0.000 claims description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 claims 14
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 claims 14
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 claims 14
- 102100038073 General transcription factor II-I Human genes 0.000 claims 5
- 101710144827 General transcription factor II-I Proteins 0.000 claims 5
- 101000596334 Homo sapiens TSC22 domain family protein 1 Proteins 0.000 claims 5
- 102100035051 TSC22 domain family protein 1 Human genes 0.000 claims 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims 5
- 101100228139 Homo sapiens GAFA1 gene Proteins 0.000 claims 3
- 102100039711 Putative uncharacterized protein GAFA-1 Human genes 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 230000001613 neoplastic effect Effects 0.000 claims 3
- 230000005909 tumor killing Effects 0.000 claims 3
- 229960005486 vaccine Drugs 0.000 claims 3
- 230000034994 death Effects 0.000 claims 2
- 208000037841 lung tumor Diseases 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 229920001184 polypeptide Polymers 0.000 claims 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims 1
- 230000001594 aberrant effect Effects 0.000 claims 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 1
- 102000009465 Growth Factor Receptors Human genes 0.000 abstract description 22
- 108010009202 Growth Factor Receptors Proteins 0.000 abstract description 22
- 229940123924 Protein kinase C inhibitor Drugs 0.000 abstract description 22
- 230000003388 anti-hormonal effect Effects 0.000 abstract description 22
- 239000003881 protein kinase C inhibitor Substances 0.000 abstract description 22
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 abstract description 17
- 230000001394 metastastic effect Effects 0.000 abstract description 6
- 230000003902 lesion Effects 0.000 abstract description 4
- 206010068771 Soft tissue neoplasm Diseases 0.000 abstract description 2
- 230000000394 mitotic effect Effects 0.000 abstract description 2
- 230000017066 negative regulation of growth Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 abstract 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 72
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 60
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 60
- RJYQLMILDVERHH-UHFFFAOYSA-N 4-Ipomeanol Chemical compound CC(O)CCC(=O)C=1C=COC=1 RJYQLMILDVERHH-UHFFFAOYSA-N 0.000 description 56
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 56
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 56
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 54
- 229960001674 tegafur Drugs 0.000 description 54
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 54
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 52
- 229940022353 herceptin Drugs 0.000 description 43
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 33
- 229960004397 cyclophosphamide Drugs 0.000 description 33
- 229960003668 docetaxel Drugs 0.000 description 32
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 31
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 31
- 108010002156 Depsipeptides Proteins 0.000 description 31
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 31
- JVHIPYJQMFNCEK-UHFFFAOYSA-N cytochalasin Natural products N1C(=O)C2(C(C=CC(C)CC(C)CC=C3)OC(C)=O)C3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 JVHIPYJQMFNCEK-UHFFFAOYSA-N 0.000 description 31
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 31
- 229950006050 spiromustine Drugs 0.000 description 31
- 229960003048 vinblastine Drugs 0.000 description 31
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 31
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 31
- 229960004528 vincristine Drugs 0.000 description 31
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 31
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 31
- 229960004355 vindesine Drugs 0.000 description 31
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 31
- 102000013462 Interleukin-12 Human genes 0.000 description 30
- 108010065805 Interleukin-12 Proteins 0.000 description 30
- 102000000588 Interleukin-2 Human genes 0.000 description 30
- 108010002350 Interleukin-2 Proteins 0.000 description 30
- 102000004388 Interleukin-4 Human genes 0.000 description 30
- 108090000978 Interleukin-4 Proteins 0.000 description 30
- 229960005243 carmustine Drugs 0.000 description 30
- 229940117681 interleukin-12 Drugs 0.000 description 30
- 229940028885 interleukin-4 Drugs 0.000 description 30
- 229960004857 mitomycin Drugs 0.000 description 30
- 229960004641 rituximab Drugs 0.000 description 30
- 229940033942 zoladex Drugs 0.000 description 30
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 29
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 description 29
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 29
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-UHFFFAOYSA-N 0.000 description 29
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 29
- 229960001220 amsacrine Drugs 0.000 description 29
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 29
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 29
- 229960002340 pentostatin Drugs 0.000 description 29
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 29
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 28
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 description 28
- ICAYNKLSQSKOJZ-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-[(4-fluorophenyl)-hydroxymethyl]piperidin-1-yl]butan-1-one Chemical compound C=1C=C(F)C=CC=1C(O)C(CC1)CCN1CCCC(=O)C1=CC=C(F)C=C1 ICAYNKLSQSKOJZ-UHFFFAOYSA-N 0.000 description 28
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 28
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 28
- OIRDTQYFTABQOQ-KQYNXXCUSA-N Adenosine Natural products C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 28
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 28
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 28
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 28
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 28
- 102000003996 Interferon-beta Human genes 0.000 description 28
- 108090000467 Interferon-beta Proteins 0.000 description 28
- 102000008070 Interferon-gamma Human genes 0.000 description 28
- 108010074328 Interferon-gamma Proteins 0.000 description 28
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 description 28
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 28
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 28
- 229910019142 PO4 Inorganic materials 0.000 description 28
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 28
- 229950008427 acivicin Drugs 0.000 description 28
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 28
- 229960005305 adenosine Drugs 0.000 description 28
- 229950005033 alanosine Drugs 0.000 description 28
- 229960002092 busulfan Drugs 0.000 description 28
- 229940088954 camptosar Drugs 0.000 description 28
- 229960004630 chlorambucil Drugs 0.000 description 28
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 28
- 229960003901 dacarbazine Drugs 0.000 description 28
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 28
- 229960000975 daunorubicin Drugs 0.000 description 28
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 28
- 229960005420 etoposide Drugs 0.000 description 28
- 229960005304 fludarabine phosphate Drugs 0.000 description 28
- 229960000908 idarubicin Drugs 0.000 description 28
- 229960001101 ifosfamide Drugs 0.000 description 28
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 28
- 229960003130 interferon gamma Drugs 0.000 description 28
- 229960001388 interferon-beta Drugs 0.000 description 28
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 28
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 28
- 229960004961 mechlorethamine Drugs 0.000 description 28
- 229960001924 melphalan Drugs 0.000 description 28
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 28
- 229960001428 mercaptopurine Drugs 0.000 description 28
- 229960000485 methotrexate Drugs 0.000 description 28
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 28
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 28
- 229960001156 mitoxantrone Drugs 0.000 description 28
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 28
- 229960001756 oxaliplatin Drugs 0.000 description 28
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 28
- 239000010452 phosphate Substances 0.000 description 28
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 28
- 229960000952 pipobroman Drugs 0.000 description 28
- 229960003171 plicamycin Drugs 0.000 description 28
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 28
- 229960001278 teniposide Drugs 0.000 description 28
- 229960001196 thiotepa Drugs 0.000 description 28
- 229960003087 tioguanine Drugs 0.000 description 28
- 229960000303 topotecan Drugs 0.000 description 28
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 28
- 229960001099 trimetrexate Drugs 0.000 description 28
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 28
- 229960001055 uracil mustard Drugs 0.000 description 28
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 27
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 27
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 27
- 229960002436 cladribine Drugs 0.000 description 27
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 27
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 27
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 27
- 229960003723 tiazofurine Drugs 0.000 description 27
- 229940035893 uracil Drugs 0.000 description 27
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 26
- 229960000684 cytarabine Drugs 0.000 description 26
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 24
- 229940127093 camptothecin Drugs 0.000 description 24
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 23
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 23
- 230000001225 therapeutic effect Effects 0.000 description 23
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 22
- 210000004748 cultured cell Anatomy 0.000 description 15
- 231100000433 cytotoxic Toxicity 0.000 description 15
- 230000001472 cytotoxic effect Effects 0.000 description 15
- 230000001404 mediated effect Effects 0.000 description 13
- 230000002441 reversible effect Effects 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 230000003463 hyperproliferative effect Effects 0.000 description 8
- 101150029707 ERBB2 gene Proteins 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000011275 oncology therapy Methods 0.000 description 6
- 210000003932 urinary bladder Anatomy 0.000 description 6
- 230000003442 weekly effect Effects 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000000824 cytostatic agent Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 4
- 201000004384 Alopecia Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 4
- 235000008191 folinic acid Nutrition 0.000 description 4
- 239000011672 folinic acid Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229960001691 leucovorin Drugs 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 150000003384 small molecules Chemical group 0.000 description 4
- 241001529936 Murinae Species 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000032823 cell division Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 230000001351 cycling effect Effects 0.000 description 3
- ADFOJJHRTBFFOF-RBRWEJTLSA-N estramustine phosphate Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 ADFOJJHRTBFFOF-RBRWEJTLSA-N 0.000 description 3
- 229960004750 estramustine phosphate Drugs 0.000 description 3
- 208000024963 hair loss Diseases 0.000 description 3
- 230000003676 hair loss Effects 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 3
- 230000008261 resistance mechanism Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 102000004374 Insulin-like growth factor binding protein 3 Human genes 0.000 description 2
- 108090000965 Insulin-like growth factor binding protein 3 Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 210000000448 cultured tumor cell Anatomy 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229940043138 pentosan polysulfate Drugs 0.000 description 2
- 229950008679 protamine sulfate Drugs 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- KGSVNOLLROCJQM-UHFFFAOYSA-N 2-(benzylamino)acetic acid Chemical compound OC(=O)CNCC1=CC=CC=C1 KGSVNOLLROCJQM-UHFFFAOYSA-N 0.000 description 1
- AWYDPLFHUNXJRH-UHFFFAOYSA-N 3,3,3-trifluoro-2-methyl-n-phenylpropanamide Chemical compound FC(F)(F)C(C)C(=O)NC1=CC=CC=C1 AWYDPLFHUNXJRH-UHFFFAOYSA-N 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- 206010006298 Breast pain Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000006662 Mastodynia Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 206010070308 Refractory cancer Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 230000001955 cumulated effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 208000018821 hormone-resistant prostate carcinoma Diseases 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 208000019420 lymphoid neoplasm Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008722 morphological abnormality Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00113—Growth factors
- A61K39/001132—Fibroblast growth factors [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- Cancer therapy such as chemotherapy and radiation, targets proliferating cells and thereby causes undesired toxicity to normal host tissues that undergo continuous renewal, including the hematopoietic cells, cells in the lining of the gastrointestinal tract, and hair follicles.
- Bone marrow suppression induced by cancer therapy is, at least in part, overcome by the use of hematopoietic growth factors, including erythropoietin, granulocytes colony-stimulating factor, and granulocyte-macrophage colony- stimulating factor (Gabrilove, J.L. and Goldie, D.W. (1993) In: Cancer, Principles & Practice of Oncology (eds. DeVita, V.T.
- the invention is based, at least in part, on the elucidation of the role played by basic Fibroblast Growth Factor (bFGF) in the induction of broad spectrum resistance to anticancer agents in a number of tumors and metastatic lesions, and the role played by acidic FGF (aFGF) in amplifying the bFGF-induced resistance.
- bFGF basic Fibroblast Growth Factor
- aFGF acidic FGF
- Inhibitors of aFGF/bFGF enhance the in vitro and in vivo activity of anticancer agents, and result in shrinkage and eradication of human xenograft tumors including lung metastasis and subcutaneous tumors in mice.
- Methods of the invention use FGF antagonists to potentiate the antitumor effect of anticancer agents.
- FGF agonists e.g., aFGF, e.g., bFGF
- Methods of the invention use FGF agonists to protect normal cells from the cytotoxic effects of anticancer agents.
- the invention features, a method of inhibiting unwanted cell growth or division, e.g., reducing or inhibiting the proliferation of, or enhancing the killing of, a cell, e.g., a hyperproliferative cell, e.g., a malignant cell or a benign hyperproliferative cell.
- the method includes: contacting the cell with at least one cytotoxic agent, (e.g., a cytostatic agent, e.g., an agent that causes cell death) and at least one FGF antagonist, in an amount, which together, is effective to reduce or inhibit the proliferation of the cell, or induce cell killing.
- the unwanted cell is the cell of an established tumor.
- the invention features a method of improving the efficacy of an agent, e.g., a cytotoxic agent, in a subject.
- the method includes: administering to the subject at least one agent, e.g., a cytotoxic agent; administering to the subject at least one FGF antagonist.
- the FGF antagonist enhances the efficacy of the agent, e.g., a cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist.
- the FGF antagonist improves the efficacy of the cytotoxic agent against a cancer, e.g., an established tumor.
- the invention features, a method of inhibiting unwanted cell growth or division, or inducing the killing of an unwanted cell (e.g., a hyperproliferative cell), e.g., a cell of an established tumor or a benign hyperproliferative cell, in a subject.
- the method can be used to treat or prevent, in a subject, a disorder characterized by unwanted cell growth or division.
- the method includes: administering to the subject at least one cytotoxic agent, (e.g., a cytostatic agent, an agent that causes cell death), and at least one FGF antagonist, in an amount, which together, is effective (e.g., therapeutically or prophylactically) to reduce or inhibit the growth or division of, or induce the killing of, the unwanted cell.
- the unwanted cell is the cell of an established tumor.
- the FGF antagonist inhibits or reduces the FGF- induced resistance to a broad spectrum of cytotoxic agents, i.e., agents with diverse structures and mechanisms of action, including but not limited to, antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway (e.g., protein kinase C inhibitors, e.g., anti-hormones, e.g., antibodies against growth factor receptors), agents that promote apoptosis and/or necrosis, interferons, interleukins, tumor necrosis factors, and radiation.
- cytotoxic agents i.e., agents with diverse structures and mechanisms of action, including but not limited to, antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, mitotic inhibitors, alkylating agents, inter
- the FGF antagonist comprises an inhibitor of bFGF. In a preferred embodiment, the FGF antagonist comprises an inhibitor of aFGF.
- the FGF antagonist includes at least one bFGF inhibitor and at least one aFGF inhibitor.
- the aFGF inhibitor potentiates the action of the bFGF inhibitor.
- the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to its receptor.
- the FGF antagonist acts intracellularly, e.g., interacts with the intracellular domain of the FGF receptor, inhibits the intracellular effects of FGF.
- the FGF antagonist is capable of binding to an FGF molecule or an FGF receptor; blocks the binding of FGF to a receptor; blocks the interaction of FGF with molecules that facilitate the binding of FGF to a receptor; and/or down regulates FGF receptor action.
- the FGF molecule is bFGF and/or aFGF.
- the FGF antagonist is other than suramin. In a preferred embodiment, the FGF antagonist is other than an antibody, e.g., an antibody against FGF or an FGF receptor.
- the FGF antagonist inhibits or reverses the resistance to anticancer drugs induced by FGF (e.g. aFGF and/or bFGF) in cultured tumor cells under in vitro conditions.
- FGF e.g. aFGF and/or bFGF
- the determination of effect on cultured cells can be determined using the system described in Example XV.
- the FGF antagonist improves the efficacy of an agent, e.g., a cytotoxic agent, in the subject, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist.
- the FGF antagonist improves the efficacy of the cytotoxic agent against an established tumor.
- the FGF antagonist is present in an amount sufficient to block FGF (e.g., bFGF and/or aFGF) action, but is not sufficient to cause one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject; and/or (iv) significant cell cycle arrest.
- FGF e.g., bFGF and/or aFGF
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- the FGF antagonist is administered at levels such that the plasma concentration of the FGF antagonist that is present when the cytotoxic agent is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that if the same concentration of FGF antagonist is provided in cultured cells at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, and most preferably at least 99% of the treated cultured cells continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with the FGF antagonist.
- the determination of effect on cultured cells should be determined with the system described in Example XV.
- the FGF antagonist is administered at levels that, although not resulting in significant cell cycle arrest, significant cell death, or significant inhibition of cell growth as described above, sensitizes the tumor cells to treatment with cytotoxic agents.
- the levels of FGF antagonist result in a significant inhibition of FGF-mediated chemoresistance, e.g., the resistance of tumor cells to cytotoxic agents that is mediated by FGF.
- the FGF antagonist inhibits at least 10, more preferably, at least 25, more preferably at least, 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, and most preferably at least 99% of the FGF-mediated chemoresistance.
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
- the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
- the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
- the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
- the FGF antagonist is a protein or a peptide; is an antibody, e.g., a monoclonal, a murine antibody or a human antibody, or an antigen- binding fragment thereof.
- the monoclonal antibody is a human antibody.
- the antibodies can be of the various isotypes, including: IgG (e.g., IgGl, IgG2, IgG3, IgG4), IgM, IgAl, IgA2, IgD, of IgE.
- the antibody is an IgG isotype.
- the antibodies can be full-length (e.g., an IgGl or IgG4 antibody) or can include only an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv or a single chain Fv fragment).
- the FGF antagonist is a recombinant antibody, e.g., a chimeric or a humanized antibody, or an antigen binding fragment thereof, e.g., has a variable region, or at least a complementarity determining region (CDR), derived from a non-human antibody (e.g., murine), while the remaining portion(s) are human in origin.
- a recombinant antibody e.g., a chimeric or a humanized antibody, or an antigen binding fragment thereof, e.g., has a variable region, or at least a complementarity determining region (CDR), derived from a non-human antibody (e.g., murine), while the remaining portion(s) are human in origin.
- CDR complementarity determining region
- the FGF antagonist is a fragment of the FGF molecule.
- the FGF fragment competes with an FGF molecule for binding to the receptor.
- the FGF antagonist is a small molecule, (e.g., is selected from a combinatorial library).
- the FGF antagonist is chosen from those disclosed herein, e.g., suramin, structural analogs of suramin, anti-FGF antibodies, anti-FGF receptor antibodies, pentosan polysulfate, scopolamine, angiostatin, sprouty, estradiol, carboxymethylbenzylamme dextran (CMDB7), suradista, insulin-like growth factor binding protein-3, ethanol, heparin (e.g., 6-O-desulfated heparin), low molecular weight heparin, heparan sulfate, protamine sulfate, transforming growth factor beta, cyclosporin A, or RNA ligands for bFGF.
- the FGF antagonist is heparin.
- the FGF antagonist is low molecular weight heparin.
- the FGF antagonist is heparan sulfate. In a preferred embodiment, the FGF antagonist is an anti-FGF antibody.
- the FGF antagonist is suramin.
- the FGF antagonist is suramin and the suramin is present in a concentration that is sufficient to block the resistance to anticancer agents induced by FGF (e.g., bFGF and/or aFGF), but is not sufficient to produce one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject, and/or (iv) cell cycle arrest.
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- the FGF antagonist is suramin and it is administered at levels such that the plasma concentration of suramin that is present when the cytotoxic agent is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that, if the same concentration of suramin is provided in cultured cells, at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, more preferably at least 99, and most preferably at least 99% of the treated cultured cells continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with suramin.
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- suramin is administered in an amount that results in a concentration ranging from about 0.1 to 100 ⁇ g/ml, preferably about 1 to 85 ⁇ g/ml, more preferably, about 5 to 60 ⁇ g/ml, even more preferably, about 10 to 50 ⁇ g/ml, and most preferably, 15 to 45 ⁇ g/ml.
- the pharmacokinetics of suramin is characterized by a triphasic concentration decline, with half-lives of 5.5 hours, 4.1 days and 78 days. The total body clearance is 0.0095 liter/hour/m 2 (Jodrell et al (1994) J Clin Oncol 12:166-175).
- an initial dose of approximately 240 mg/m 2 should be administered to the average patient to achieve plasma concentrations declining from about 90 ⁇ g/ml (63 ⁇ M) to about 18 ⁇ g/ml (13 ⁇ M) over 96 hours.
- the 96 hour duration is chosen as an example, as the plasma concentrations of many commonly used cytotoxic agents to be administered with suramin will have declined below their therapeutic levels at 96 hours.
- Similar calculations can be performed to identify the initial suramin dose to deliver the preferred suramin plasma concentrations over other desired treatment durations. Maintenance doses to adjust the plasma concentrations for later treatment cycles can be similarly calculated.
- the total suramin exposure is preferably less than
- 800 ⁇ M-day over 96 hours preferably less than 600 ⁇ M-day over 96 hours, preferably less than 500 ⁇ M-day over 96 hours, preferably less than 400 ⁇ M-day over 96 hours, preferably less than 300 ⁇ M-day over 96 hours, preferably less than 252 ⁇ M-day over 96 hours, preferably less than 200 ⁇ M-day over 96 hours, preferably less than 150 ⁇ M- day over 96 hours, preferably less than 100 ⁇ M-day over 96 hours, and most preferably less than 52 ⁇ M-day over 96 hours.
- the total suramin exposure is a product of the drug plasma concentration in ⁇ M-day (e.g., the average micromolarity over 24 hours) and the treatment duration in days. For example, treatment of a subject with 13 ⁇ M of suramin for four days would result in a total drug exposure of 52 ⁇ M-day over 96 hours.
- suramin is administered in an amount that results in a plasma concentration of less than 100, preferably less than 80, preferably less than 50, preferably less than 25, more preferably less than 15, and most preferably less than 10 ⁇ M.
- this plasma concentration is maintained for less than 20 days, preferably less than 15 days, preferably less than 12 days, preferably less than 10 days, more preferably less than 8 days, and most preferably less than 5 days beyond the time duration where therapeutic concentrations of a cytotoxic agent are maintained.
- the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
- suramin is given immediately or within 3, 2, or 1 day before the administration of the cytotoxic agent, ending immediately after plasma concentrations of the cytotoxic agent are below the therapeutic level.
- the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
- the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
- the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
- Methods described herein use suramin to enhance the antitumor effect of a cytotoxic agent (e.g., agents described in Table 2), where the suramin dose is selected to deliver a plasma concentration of below 100 ⁇ g/ml, preferably below 75 ⁇ g/ml, most preferably below 50 ⁇ g/ml, in a mammal while the cytotoxic agent is present in plasma at a pharmacologically active concentration.
- the suramin dose is administered before, simultaneously with, or after the administration of the at least one anticancer agent.
- mice with two weekly intravenous bolus suramin doses of 10 mg/kg for 3 weeks enhances the antitumor effect of anticancer drugs (e.g., paclitaxel, doxorubicin) but does not result in additional body weight loss.
- This dose is calculated to result in a plasma suramin concentration of about 10 ⁇ M (-14 ⁇ g/ml) at 72 hours after dose administration (see Example IX, Tables 4 and 5, Figure 7).
- the methods of the art use high dose suramin, either alone or in combination with a cytotoxic agent, where for a human subject, maintenance of plasma suramin concentrations of between 150 to 300 ⁇ g/ml is needed to produce a measurable antitumor effect (Eisenberger et al (1995) J Clin Oncol 13:2174-2186).
- a typical suramin dosing schedule aimed at maintaining suramin plasma concentrations between 150 and 300 ⁇ g/ml consists of an initial administration of 2100 mg/m 2 over the first week with the subsequent doses repeated every 28 days for 6 months or longer; the subsequent doses are adjusted using the Bayesian pharmacokinetic method (Dawson et al (1998) Clin Cancer Res 4:37-44, Falcone et al (1999) Cancer 86:470- 476).
- the methods of the art for using suramin in combination with other cytotoxic agents often administer suramin at a more frequent schedule or a longer duration than the frequency and the treatment duration for the other cytotoxic agents.
- the duration of doxorubicin treatment was up to 20 weeks whereas the duration of the suramin treatment was up to 45 weeks (Tu et al (1998) Clin Cancer Res 4:1193-1201).
- suramin was given weekly whereas mitomycin C was given only every 5 weeks (Rapoport et al (1993) Ann Oncol 4:567-573).
- suramin causes the following toxicity in a human patient: adrenal insufficiency, coagulopathy, peripheral neuropathy, and proximal muscle weakness (Dorr and Von Hoff, Cancer Chemotherapy Handbook, 1994, pp 859-866).
- the incidence and severity of these toxicities are positively related to cumulated dose and are minimized in the methods described herein.
- the FGF antagonist is an anti-FGF antibody.
- the anti-FGF antibody is present in a concentration that is sufficient to block the resistance to anticancer agents induced by FGF (e.g., bFGF and/or aFGF), but is not sufficient to produce one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject, and/or (iv) cell cycle arrest.
- the FGF antagonist is an anti-FGF antibody and it is administered at levels such that the plasma concentration of the anti-FGF antibody that is present when the cytotoxic agent is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that if the same concentration of the anti-FGF antibody is provided in cultured cells at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, more preferably at least 99, and most preferably at least 99% of the treated cultured cells, continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with the FGF antibody.
- the determination of effect on cultured cells can be determined with the system described
- the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti- FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
- the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti- FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
- the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti- FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
- the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti- FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
- the method inhibits the proliferation of, or enhances the killing of, a hyperproliferative cell selected from the group consisting of a solid tumor cell, a soft-tissue tumor cell, a metastatic tumor cell, a leukemic tumor cell, and a lymphoid tumor cell.
- a hyperproliferative cell selected from the group consisting of a solid tumor cell, a soft-tissue tumor cell, a metastatic tumor cell, a leukemic tumor cell, and a lymphoid tumor cell.
- the method inhibits the proliferation of, or enhances the killing of, a hyperproliferative cell in a fibrotic tumor.
- the disorder is a cancer, e.g., a sarcoma, a carcinoma, an adenocarcinoma, a lymphoma, or a leukemia.
- the disorder is a cancer which includes an established tumor.
- the disorder is a cancer which includes a solid tumor.
- the disorder is a cancer which includes a metastatic lesion.
- the disorder is a cancer which includes a leukemia.
- the disorder is a cancer which includes a lymphoma.
- the disorder is a cancer, e.g., a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma
- the disorder includes a cancer which includes cells, e.g., tumor or metastatic cells, which form from a tissue where an FGF molecule is expressed, preferably at high levels, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
- a cancer which includes cells, e.g., tumor or metastatic cells, which form from a tissue where an FGF molecule is expressed, preferably at high levels, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
- the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system.
- cells e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system.
- the disorder is a cancer which includes an established tumor, e.g., a tumor that has been growing in a subject for at least one week, preferably two weeks, preferably one month, preferably two months, more preferably three months, more preferably six months, and most preferably longer than six months.
- an established tumor e.g., a tumor that has been growing in a subject for at least one week, preferably two weeks, preferably one month, preferably two months, more preferably three months, more preferably six months, and most preferably longer than six months.
- an established tumor can be diagnosed clinically.
- an established tumor can be visualized on diagnostic media, e.g., an X-ray, a CAT scan, or MRI.
- diagnostic media e.g., an X-ray, a CAT scan, or MRI.
- an established tumor can be diagnosed by the detection of tumor markers, e.g., prostate specific antigen for prostate cancer, Her2/neu for certain breast cancers, CA125 for ovarian cancer, or genetic alterations.
- an established tumor can be diagnosed by the detection of pathological changes, e.g., blood in sputum for lung cancer, blood in feces in colon cancer, blood in urine for bladder cancer, a lump in breasts for breast cancer, pain, or headache.
- pathological changes e.g., blood in sputum for lung cancer, blood in feces in colon cancer, blood in urine for bladder cancer, a lump in breasts for breast cancer, pain, or headache.
- an established tumor can be diagnosed by biochemical analysis of a patient sample, e.g., a patient's sputum, feces, urine, etc.
- an established tumor can be diagnosed by morphological analysis of cells derived from a subject, e.g., morphological abnormalities, abnormal nucleus-to- cytoplasmic ratios, abnormal tissue architecture, abnormal tissue organization, or abnormal tissue composition.
- an established tumor is one that is visible, palpable, or found during necropsy or autopsy.
- the disorder includes a cancer, e.g., lung cancer, renal cancer, glioma, melanoma, or chemotherapy-refractory cancer, a metastatic cancer, which is chemoresistant, e.g., shows little or no significant response to chemotherapy.
- a cancer e.g., lung cancer, renal cancer, glioma, melanoma, or chemotherapy-refractory cancer, a metastatic cancer, which is chemoresistant, e.g., shows little or no significant response to chemotherapy.
- the hyperproliferative cell is found in a benign lesion.
- the disorder is selected from the group consisting of psoriasis, cysts, benign prostatic hyperplasia, and endometriosis.
- the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn's disease, hepatic adenoma, hepatic cirrhosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the group consisting of benign hyperplastic diseases,
- the subject is a mammal, e.g., a human.
- the subject is a patient, e.g., a cancer patient.
- the subject can be a patient with non-small cell lung cancer, is treated with a combination of paclitaxel, carboplatin and an FGF antagonist, e.g., suramin, or with a combination of gemcitabine, cisplatin, and an FGF antagonist, e.g., suramin.
- the subject can be a patient with hormone refractory prostate cancer, who is treated with a combination of estramustine phosphate, taxotere and an FGF antagonist, e.g., suramin, or with a combination of doxorubicin, ketoconazole and an FGF antagonist, e.g., suramin.
- the subject can be a patient with metastatic breast cancer, who is treated with a combination of cyclophosphamide, doxorubicin, 5- fluorouracil and an FGF antagonist, e.g., suramin, or a combination of doxorubicin, taxotere and an FGF antagonist, e.g., suramin.
- the subject can be a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with a HER2/neu inhibitor (e.g., a HER2/neu antibody) and an FGF antagonist, e.g., suramin, with or without paclitaxel or cisplatin.
- a HER2/neu inhibitor e.g., a HER2/neu antibody
- an FGF antagonist e.g., suramin
- the subject can be a patient with advanced or metastatic colorectal cancer, who is treated with a combination of irinotecan and an FGF antagonist, e.g., suramin.
- the subject can be a patient with advanced colon cancer, who is treated with a combination of 5-fluorouracil, leucovorin and an FGF antagonist, e.g., suramin.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an agent that promotes apoptosis and/or necrosis e.g., an interferon, an interleukin, a tumor necros
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interleukin e.g., a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interleukin e.g., interleukin, and radiation.
- the cytotoxic agent is selected from those disclosed below.
- the cytotoxic agent is selected from those disclosed below.
- the cytotoxic agent is selected from those disclosed below.
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine
- Ara-C trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl- L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5- fluoro-2'-deoxyuridine, 5-fluorouridine, 5'-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphat
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA)
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA)
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA)
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L- Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxy
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere(e.g., Docetaxel), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin,
- paclitaxel paclitaxel, vincristine, vinblastine, vindesine, vinore
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA)
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA)
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy- 2-methyl-3 '-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interleukin 2, interleukin 4, interleukin 12, and radiation.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 e.g
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- paclitaxel gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- Her2/neu antibody e.g
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, taxotere, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is present in an amount equal to or lower than the one used in conventional chemotherapy.
- the dose of paclitaxel is equal to or below 225 mg/m 2
- the dose of carboplatin is chosen to achieve a total concentration-time product of equal to or below 6-7 mg/ml.min in previously untreated patients, or equal to or below 4-5 mg/ml.min in patients that have received chemotherapy previously; the treatment is repeated every 3 weeks.
- estramustine phosphate and taxotere with an FGF antagonist
- the daily oral dose of estramustine is equal to or below 1400 mg
- the dose of taxotere is equal to or below 70 mg/m over 1 hour; the treatment is repeated every 3 weeks.
- the weekly dose of doxorubicin is equal to or below 20 mg/m 2 by 24 hr infusion
- the total daily oral dose of ketoconazole is equal to or below 1200 mg.
- the dose of intravenous cyclophosphamide is equal to or below 500 mg/m 2
- the dose of doxorubicin is equal to or below 50 mg/m 2
- the dose of 5-fluorouracil is equal to or below 500 mg/m 2
- the treatment is repeated every 4 weeks (the 5-fluorouracil dose is given once per week for two weeks whereas the doses of doxorubicin and cyclophosphamide are given once every 4 weeks).
- the Herceptin dose is equal to or below 250 mg on day 0, followed by 9 weekly doses of equal to or below 100 mg, and the cisplatin dose is equal to or below 75 mg/m 2 on days 1, 29, and 57.
- the four weekly doses of irinotecan are equal to or below 125 mg/m 2 ; the treatment cycle is 4 weeks on and 2 weeks off.
- the dose of irinotecan is 350 mg/m 2 every 3 weeks.
- the five daily intravenous bolus doses of 5-fluorouracil are equal to or below 425 mg/m 2
- the five daily intravenous bolus doses of leucovorin are equal to or below 20 mg/m 2 ;
- the treatment cycle is 1 week on and 4 weeks off.
- the three weekly doses of gemcitabine are equal to or below 1000 mg/m 2
- the single cisplatin dose given on day 2 is equal to or below 100 mg/m ; the treatment is repeated every 4 weeks.
- the method further includes repeated dosages of the same, or a different cytotoxic agent.
- the method further includes repeated dosages of the same, or a different FGF antagonist.
- the cytotoxic agent and the FGF antagonist are administered at the same time or in overlapping time periods; the agent and the FGF antagonist are administered at different times; the agent is administered first and the FGF antagonist is administered subsequently; the FGF antagonist is administered first and the agent is administered subsequently.
- the cytotoxic agent is administered systemically or locally.
- the agent can be administered parenterally (e.g., subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, intrathecally, etc.), intravesically (i.e., urinary bladder), intraprostatically, orally, nasally, rectally, topically, and/or transdermally.
- the FGF antagonist is administered systemically or locally.
- the FGF antagonist can be administered parenterally (e.g., subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, intrathecally, etc.), intravesically (i.e., urinary bladder), intraprostatically, orally, nasally, rectally, topically, and/or transdermally.
- the methods described herein further comprise monitoring the FGF levels (e.g., a-FGF and/or b-FGF) of a subject prior to or during treatment.
- the amount of an FGF antagonist administered to the subject is determined based upon the levels of FGF present in the subject, e.g., low concentrations of FGF in the subject require decreased doses of the FGF antagonist to overcome the chemoresistance mediated by FGF.
- the invention features, a method of treating a cell, e.g., inhibiting cell killing, or protecting the ability of a cell (e.g., a dividing cells, preferably, a rapidly dividing cell) to proliferate, e.g., a method of protecting a rapidly dividing cell, in a subject, from one or more of killing, inhibition of growth or division or other damage caused, e.g., by a cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death).
- the method includes: administering, to the subject, an effective amount of at least one FGF agonist, thereby treating the cell, e.g., protecting or reducing the damage to the dividing cell from said cytotoxic agent.
- the cell is: a cell from a body surface or cavity, e.g., a cell of the gastrointestinal or esophageal tract; a hair follicle cell; a hematopoietic cell, e.g., a hematopoietic stem cell.
- the cell is part of the lining of the gastrointestinal tract or the esophageal tract.
- the method inhibits hair loss; inhibits weight loss; inhibits the loss of gastrointestinal function; inhibits the loss of hematopoiesis.
- the method further includes administering at least one cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death), e.g., an antiproliferative agent, e.g., an anticancer drug, e.g. radiation, e.g., an interferon, e.g., an interleukin, e.g., a tumor necrosis factor, to said subject.
- cytotoxic agent e.g., a cytostatic agent, e.g., an agent that causes cell death
- an antiproliferative agent e.g., an anticancer drug
- radiation e.g., an interferon, e.g., an interleukin, e.g., a tumor necrosis factor
- the cytotoxic agent is other than radiation, e.g., is an administered compound.
- the cytotoxic agent is a compound other than an antimetabolite.
- the FGF agonist is administered orally, locally, e.g., topically, or ex vivo.
- the FGF agonist can be applied topically to treat hair follicles.
- the cell e.g., a bone marrow cell, can be treated ex vivo.
- the FGF agonist is administered locally to a site, e.g., gastrointestinal tract, bone marrow, or the skin.
- a site e.g., gastrointestinal tract, bone marrow, or the skin.
- the FGF agonist is directly injected into the bone marrow.
- the FGF agonist is applied topically, e.g. externally to the scalp.
- the application of the FGF agonist does not significantly result in absorption into systemic circulation, and/or does not significantly result in a blood or plasma concentration that is sufficient to increase the proliferation of a tumor cell in the subject.
- the FGF agonist is administered to a subject by a method that does not result in significant systemic administration or significant systemic levels of the FGF agonist, e.g. does not result in an increase in FGF agonist blood levels that promotes the chemoresistance of the tumor.
- Systemic administration or levels of the FGF agonist can be evaluated by determining the level of the FGF agonist in the blood before and after its administration to a subject. These two levels can then be tested in vitro and compared for their effect on the antitumor effect mediated by a cytotoxic agent against tumor cells.
- the FGF agonist blood level after administration should increase the IC o of the cytotoxic agent by less than 30, preferably less than 20, preferably less than 10, preferably less than 5, and most preferably less than 1%, as compared to the IC 5 o of the cytotoxic agent in the presence of the blood levels of the FGF agonist prior to administration of the FGF agonist to the subject.
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- the subject is a mammal, e.g., a human.
- the subject is a patient, e.g., a cancer patient.
- the subject is a patient with non-small cell lung cancer, who is treated with a combination of two or more of: paclitaxel, carboplatin, or an FGF antagonist, e.g., suramin, or with a combination of two or more of: gemcitabine, cisplatin, or an FGF antagonist, e.g., suramin.
- the patient is a patient with hormone refractory prostate cancer, who is treated with a combination of two or more of: estramustine phosphate, taxotere, or an FGF antagonist, e.g., suramin, or with a combination of two or more of: doxorubicin, ketoconazole, an FGF antagonist, e.g., suramin.
- the patient is a patient with metastatic breast cancer, who is treated with a combination of two or more of: cyclophosphamide, doxorubicin, 5-fluorouracil, or an FGF antagonist, e.g., suramin.
- the patient is a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with Herceptin and suramin, with or without paclitaxel or cisplatin.
- the patient is a patient with advanced or metastatic colorectal cancer, who is treated with one or more of: irinotecan or an FGF antagonist, e.g., suramin.
- the patient is a patient with advanced colon cancer, who is treated with a combination of two or more of: 5-fluorouracil, leucovorin, or an FGF antagonist, e.g., suramin.
- the treatment protects said cell from an effect, e.g., a cytotoxic effect (e.g., cytostasis, e.g., cell kill, e.g., hair loss), of said cytotoxic treatment.
- a cytotoxic effect e.g., cytostasis, e.g., cell kill, e.g., hair loss
- the FGF agonist comprises bFGF, aFGF, or bFGF and aFGF, or a fragment or an analog thereof.
- bFGF and aFGF may have an additive effect, preferably, a synergistic effect.
- the FGF agonist is administered in an amount that results in concentrations sufficient to protect said cell from an effect, e.g., a cytotoxic effect (e.g., cytostasis, e.g., cell kill, e.g., hair loss), of said cytotoxic treatment.
- a cytotoxic effect e.g., cytostasis, e.g., cell kill, e.g., hair loss
- Administration of the FGF agonist may be repeated to provide protection throughout the duration of said cytotoxic treatment and/or throughout the duration when the plasma concentrations of the cytotoxic agent remain sufficient to produce a cytotoxic effect.
- the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
- the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
- the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
- the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
- the FGF agonist is a peptide, or a small molecule.
- the FGF agonist is nonproteinaceous.
- the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti- hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti- hormone, e.g., an antibody against growth factor receptors
- an agent that promotes apoptosis and/or necrosis e.g., an anti- hormone, e.g.,
- the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti- hormone, e.g., an antibody against growth factor receptors, an interferon, an interleukin, and a tumor necrosis factor.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti- hormone, e.g., an antibody against growth factor receptors, an interferon, an interleukin, and a tumor necrosis factor.
- the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor.
- the cytotoxic agent used in the methods described herein is chosen from those disclosed below.
- cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxycytidine, adenosine,
- cytotoxic agent used in the methods described herein, is chosen from those disclosed below.
- the cytotoxic agent used in the methods described herein is chosen from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L- Asparate (PALA), 5-fluorouracil, met
- the cytotoxic agent used in the methods described herein is chosen from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphat
- taxotere e.
- the cytotoxic agent used in the methods described herein is chosen from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphat
- taxotere e.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluororuacil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (Lupron) and flutamide.
- the invention features, a pharmaceutical composition which includes at least one FGF antagonist, at least one cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death), and a pharmaceutically acceptable carrier, wherein said FGF antagonist is present in an amount effective to enhance the efficacy of the cytotoxic agent, in reducing or inhibiting the proliferation, or in enhancing the killing, of a hyperproliferative cell.
- cytotoxic agent e.g., a cytostatic agent, e.g., an agent that causes cell death
- a pharmaceutically acceptable carrier wherein said FGF antagonist is present in an amount effective to enhance the efficacy of the cytotoxic agent, in reducing or inhibiting the proliferation, or in enhancing the killing, of a hyperproliferative cell.
- the pharmaceutical composition is packaged with directions to practice the methods described herein.
- the pharmaceutical composition includes: an inhibitor of bFGF; an inhibitor of aFGF; or a bFGF inhibitor and an aFGF inhibitor.
- the FGF antagonist inhibits or reverses the resistance to anticancer drugs induced by FGF (e.g. aFGF and/or bFGF) in cultured tumor cells under in vitro conditions.
- FGF e.g. aFGF and/or bFGF
- the determination of effect on cultured cells can be determined with the system described in Example XV.
- the FGF antagonist inhibits or reduces the resistance of tumor cells to a broad spectrum of cytotoxic agents.
- the FGF antagonist is capable of binding to an FGF molecule or an FGF receptor; blocks the binding of FGF to a receptor; blocks the interaction of FGF to molecules that facilitate the binding of FGF to a receptor; down regulates FGF receptor action; is a protein or a peptide; is an antibody, e.g., a monoclonal, diabody, a murine antibody, a human antibody, a humanized or a chimeric antibody, or an antigen-binding fragment thereof, e.g., an Fab, F(ab')2, Fv or a single chain Fv fragment; is a truncated FGF molecule, or a fragment thereof.
- the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to the extracellular domain of the FGF receptors.
- the FGF antagonist acts intracellularly, e.g., inhibits the binding of an FGF molecule to the intracellular domain of the FGF receptors.
- the FGF antagonist acts intracellularly, e.g., inhibits the intracellular effects of FGF.
- the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to its receptor.
- the FGF antagonist is chosen from those disclosed herein, e.g., suramin, structural analogs of suramin, anti-FGF antibodies, anti-FGF receptor antibodies, pentosan polysulfate, scopolamine, angiostatin, sprouty, estradiol, carboxymethylbenzylamine dextran (CMDB7), suradista, insulin-like growth factor binding protein-3, ethanol, heparin (e.g., 6-O-desulfated heparin), low molecular weight heparin, heparan sulfate, protamine sulfate, transforming growth factor beta, cyclosporin A, or RNA ligands for bFGF.
- CMDB7 carboxymethylbenzylamine dextran
- the FGF antagonist is suramin.
- the FGF antagonist is a fragment of the FGF molecule which competes with an FGF molecule for binding to the receptor; the FGF antagonist is a small molecule.
- the FGF antagonist is a small molecule, is chosen from a combinatorial library.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interferon e.g., an interleukin, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interleukin e.g., a tumor necrosis factor, and radiation.
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an interleukin e.g., interleukin, and radiation.
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L- As
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA),
- paclitaxel
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-Asparate (PALA), pen
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl- L- Asparate (PALA), pen
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L- As
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L- Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L- Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxycytidine, a
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L- Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2'-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is selected from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy- 2-methyl-3'-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti- CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
- cytotoxic agents include:
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- paclitaxel gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- Her2/neu antibody e.g
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, taxotere, doxorubicin, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, epirubicin, 5- fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- anti-Her2/neu antibody e.g., Herceptin
- anti-CD20 anti-CD20
- leuprolide e.g., Lupron
- flutamide flutamide
- the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, taxotere, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
- the cytotoxic agent is present at an amount equal to or lower than the one used in conventional chemotherapy.
- the hyperproliferative cell is a cancer cell.
- the hyperproliferative cell is found in a benign lesion.
- the disorder is selected from the group consisting of psoriasis, cysts, benign prostatic hyperplasia, and endometriosis.
- the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn's disease, hepatic adenoma, hepatic ci ⁇ hosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia,
- benign hyperplastic diseases e.g
- the invention features, a pharmaceutical composition which includes at least one FGF agonist, and a pharmaceutically acceptable carrier, wherein said FGF agonist is present in an amount effective to protect, or reduce the damage, a cell, e.g., a rapidly dividing cell, from said cytotoxic agent.
- the pharmaceutical composition is packaged with directions to practice the methods described herein.
- the FGF agonist comprises bFGF; aFGF; or bFGF and aFGF, or a fragment or an analog thereof.
- the FGF agonist comprises bFGF, or a fragment or an analog thereof.
- the FGF agonist is a peptide, or a small molecule.
- the FGF agonist is nonproteinaceous.
- the cell is: a cell from a body surface or cavity, e.g., a cell of the gastrointestinal or esophageal tract; a hair follicle cell; a hematopoietic cell, e.g., a hematopoietic stem cell.
- the cell is a part of the lining of the gastrointestinal tract or the esophageal tract.
- kits for carrying out the combined administration of the FGF antagonist/agonist with other cytotoxic agents comprises an FGF antagonist/agonist formulated in a pharmaceutical carrier, and at least one cytotoxic agent, formulated, as appropriate, in one or more separate pharmaceutical preparations.
- the kit includes directions to practice the methods described herein.
- the invention features a vaccine comprising an FGF polypeptide, or a FGF receptor-derived polypeptide, or a fragment of a proteoglycan that facilitates the binding of FGF to its receptors, and a pharmaceutically acceptable carrier, in an amount effective to immunize a subject against a neoplastic disease.
- the immunization against the neoplastic disease can be partial or complete.
- Said vaccine can be used to treat a cancer patient, or to prevent one or more of: the occu ⁇ ence of, recidivism of, and/or metastasis of, the neoplastic disease. For example, it could be administered to a patient who has had a tumor surgically removed, to prevent recurrence of the tumor.
- the subject is a mammal, e.g., a human.
- the subject is not a cancer patient.
- the subject is a pateint that is afflicted with an ailment caused by a benign hyperplasia of a normal tissue.
- the subject is a patient, e.g., a cancer patient.
- the subject can be a patient in remission, or a cancer patient undergoing treatment (e.g., conventional chemotherapy, alone or in combination, with the methods described herein).
- the subject can be a patient with non-small cell lung cancer, treated with a combination of two or more of: paclitaxel, carboplatin or an FGF antagonist, e.g., suramin, or with a combination of two or more of: gemcitabine, cisplatin, or an FGF antagonist, e.g., suramin.
- the subject can be a patient with hormone refractory prostate cancer, who is treated with a combination of two or more of: estramustine phosphate, taxotere, or an FGF antagonist, e.g., suramin, or with a combination of two or more of: doxorubicin, ketoconazole, or an FGF antagonist, e.g., suramin.
- the subject can be a patient with metastatic breast cancer, who is treated with a combination of two or more of: cyclophosphamide, doxorubicin, 5-fluorouracil, or an FGF antagonist, e.g., suramin, or a combination of two or more of: doxorubicin, taxotere, or an FGF antagonist, e.g., suramin.
- the subject can be a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with a HER2/neu inhibitor (e.g., a HER2/neu antibody) and/or an FGF antagonist, e.g., suramin, with or without paclitaxel or cisplatin.
- the subject can be a patient with advanced or metastatic colorectal cancer, who is treated with one or more of: irinotecan or an FGF antagonist, e.g., suramin.
- the subject can be a patient with advanced colon cancer, who is treated with a combination of two or more of: 5- fluorouracil, leucovorin, or an FGF antagonist, e.g., suramin.
- the subject can be a patient that is in remission but is with a cancer that has a good likelihood to recur, e.g., adult leukemia, e.g., early disseminated prostate cancer.
- the invention features, a method for evaluating the effectiveness of a compound, e.g., for treating a disorder, e.g., a proliferative disorder, e.g., a malignant disorder, or for protecting cells, e.g., from a cytotoxic agent.
- the method includes: contacting the compound with an FGF, e.g., aFGF or bFGF; and evaluating the ability of the compound to inhibit or promote FGF activity, inhibition being co ⁇ elated with effectiveness of treating a disorder, and promotion being co ⁇ elated with cell protection.
- an FGF e.g., aFGF or bFGF
- the method further comprises testing the compound to determine if it can modulate, e.g., increase, the efficacy of an agent which kills cells or inhibits cell growth, e.g., an anticancer agent. This can be done by administering the compound and the agent, together or separately, to a test cell or organism.
- the method further comprises testing the compound to determine if it can modulate, e.g., increase, the efficacy of an agent which kills cells or inhibits cell growth, e.g., an anticancer agent, in the presence of FGF (e.g., bFGF, and or aFGF).
- FGF e.g., bFGF, and or aFGF
- the method further comprises testing the compound to determine if it can protect cells from an agent that kills cells or inhibits cell growth, e.g., a cytotoxic or an anticancer agent. This can be done by administering both the compound and the agent, together or separately, to a test cell or organism.
- the method includes: providing a cell, e.g., a cultured cell, a transformed cell, a cell from a cancer, or a test organism; administering said compound to said cell (or test organism) and evaluating FGF activity, cell proliferation, cell death, or tumor growth, e.g., metastatic tumor growth.
- the disorder is a cancer which includes a sarcoma, a carcinoma, an adenocarcinoma, a lymphoma, or a leukemia.
- the disorder is a cancer which includes a solid tumor.
- the disorder is a cancer which includes a leukemia. In a prefe ⁇ ed embodiment, the disorder is a cancer which includes a lymphoma. In a prefe ⁇ ed embodiment, the disorder is a cancer which includes a metastatic lesion.
- the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue where an FGF molecule is expressed, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
- cells e.g., metastatic cells, which form from a tissue where an FGF molecule is expressed, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
- the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system.
- cells e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system.
- the disorder is a cancer, e.g., a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma
- a cancer e.g.
- the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn's disease, hepatic adenoma, hepatic ci ⁇ hosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia,
- benign hyperplastic diseases e.g
- the compound is a chemical, e.g., a small molecule (e.g., a member of a combinatorial library).
- the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, or radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- an agent that promotes apoptosis and/or necrosis e.g., an interferon, an interleukin, a tumor necros
- the cytotoxic agent is chosen from those disclosed below.
- Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N- Phosphoracetyl-L-A
- the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, a HER2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (Lupron) and flutamide.
- a HER2/neu antibody e.g., Herceptin
- anti-CD20 e.g., leuprolide (Lupron) and flutamide.
- the cell is a rapidly dividing cell, a gastrointestinal cell, or a hair follicle cell, or a hematopoietic cell, e.g., a hematopoietic stem cell.
- the invention features, a method of analyzing a sample, e.g., for the level of tumor resistance to anticancer agents.
- the method includes: evaluating the level of one or more FGF genes or gene products, wherein an increase or decrease in the level of one or more FGF genes or gene products, relative to a control, indicates the presence of tumor resistance to anticancer agents.
- the sample e.g. a sample form a subject, is a sample of tissue having unwanted proliferation, e.g., a sample of a benign hype ⁇ lasic tissue, a sample from a primary tumor, a metastatic tumor, or a leukemia.
- the expression of FGF genes or gene products is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional
- the method is performed: on a sample from a mammal, a sample from a human subject; and a sample from a cancer patient; as part of therapeutic decision making; to determine if the individual from which the target FGF is taken should receive a drug or other treatment; to diagnose an individual for a disorder or for predisposition to resistance to treatment, to stage a disease or disorder.
- the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, e.g. a particular FGF antagonist, or a dosage thereof, based on the level of FGF expression.
- nucleic acid (or protein) from the cell or sample is analyzed on positional a ⁇ ays, e.g., DNA-chip a ⁇ ays.
- the method further includes: analyzing the sample by providing an a ⁇ ay of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the a ⁇ ay, and wherein each positional distinguishable capture probe includes a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product; hybridizing the sample with the a ⁇ ay of capture probes, thereby analyzing the sample sequence.
- a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product
- the method includes a method of staging a disorder, e.g., a proliferative disorder, e.g., a benign hype ⁇ lastic disorder, e.g., a malignant disorder, in a subject.
- the method includes: providing a sample, e.g., cancerous sample, e.g.
- a tissue e.g., urine, blood, or CSF, a biopsy, from said subject; evaluating the expression of one or more FGF genes, e.g., by contacting said cancerous sample with, a nucleic acid probe that selectively hybridizes to one or more FGF gene products; wherein an increase in the level of said one or more FGF genes or gene products, relative to a control, indicates a stage in the disorder, e.g., the malignant disorder.
- a tissue e.g., a bodily fluid, e.g., urine, blood, or CSF, a biopsy
- evaluating the expression of one or more FGF genes e.g., by contacting said cancerous sample with, a nucleic acid probe that selectively hybridizes to one or more FGF gene products; wherein an increase in the level of said one or more FGF genes or gene products, relative to a control, indicates a stage in the disorder, e.g., the malignant disorder.
- the FGF genes or gene products are selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
- the method is performed: on a sample from a mammal, a sample from a human subject; e.g., a sample of a patient suffering from a benign hype ⁇ lastic disorder, e.g., a sample from a cancer patient; to determine if the individual from which the target nucleic acid or protein is taken should receive a drug or other treatment; to diagnose an individual for a disorder or for predisposition to resistance to treatment, to stage a disease or disorder.
- the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, or a dosage thereof, based on the level of FGF expression.
- the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element e.g., promoter.
- a signal entity e.g., a green fluorescent protein or other marker protein
- nucleic acid (or protein) from the cell or sample is analyzed on positional a ⁇ ays, e.g., DNA-chip arrays.
- the method further includes: analyzing the sample by providing an a ⁇ ay of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the a ⁇ ay, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product; hybridizing the sample with the a ⁇ ay of capture probes, thereby analyzing the sample sequence.
- a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product
- the invention features, a method of diagnosing a disorder, e.g., a proliferative disorder, e.g., a malignant disorder, e.g., a benign hype ⁇ roliferative disorder, in a subject.
- a proliferative disorder e.g., a malignant disorder, e.g., a benign hype ⁇ roliferative disorder
- the method includes: providing a sample e.g., a cancerous sample, e.g., a tissue, a bodily fluid (e.g., blood, urine, sputum, CSF), a biopsy, from said patient; evaluating the expression of one or more FGF genes, e.g., by contacting said sample with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF gene products; wherein an increase or decrease in the level of said one or more FGF genes or gene products, relative to a control, indicates the presence or absence of the disorder, e.g., the malignant disorder.
- a sample e.g., a cancerous sample, e.g., a tissue, a bodily fluid (e.g., blood, urine, sputum, CSF), a biopsy
- evaluating the expression of one or more FGF genes e.g., by contacting said sample with, a nucle
- the FGF related genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
- the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control of or an FGF gene control element, e.g., promoter.
- a signal entity e.g., a green fluorescent protein or other marker protein
- an FGF gene control element e.g., promoter.
- nucleic acid (or protein) from the cell or sample is analyzed on positional a ⁇ ays, e.g., DNA-chip a ⁇ ays.
- the method further includes: analyzing the sample by providing an a ⁇ ay of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the a ⁇ ay, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product; hybridizing the sample with the a ⁇ ay of capture probes, thereby analyzing the sample sequence.
- a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product
- the invention features, a method for evaluating the efficacy of a treatment of a disorder, e.g., a proliferative disorder, e.g., a malignant disorder, in a patient, comprising: providing a sample, e.g., a cancerous sample, e.g., a tissue, a bodily fluid (e.g., blood, urine, sputum, CSF), a biopsy, from said patient; evaluating the expression of one or more FGF genes, e.g., by contacting said cancerous sample with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF gene products; wherein a change, e.g., decrease, e.g., increase, in the level of said one or more FGF genes or gene products in a sample obtained after treatment, relative to the level of expression before treatment, is indicative of the efficacy of the treatment of said disorder.
- a change e
- the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, or a dosage thereof, based on the level of FGF expression.
- a therapeutic modality e.g., a particular anticancer treatment, or a dosage thereof
- the FGF genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
- the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element, e.g., promoter.
- a signal entity e.g., a green fluorescent protein or other marker protein
- an FGF gene control element e.g., promoter.
- the nucleic acid (or protein) from the cell or sample is analyzed on positional a ⁇ ays, e.g., DNA-chip a ⁇ ays.
- the method further includes: analyzing the sample by providing an a ⁇ ay of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the a ⁇ ay, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product; hybridizing the sample with the a ⁇ ay of capture probes, thereby analyzing the sample sequence.
- a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product
- the invention features, a method for evaluating the effectiveness of a treatment, e.g., the administration of a compound, for treating a disorder, e.g., a proliferative disorder, e.g., a malignant disorder.
- a treatment e.g., the administration of a compound
- a disorder e.g., a proliferative disorder, e.g., a malignant disorder.
- the method includes: providing a cell, e.g., a cultured cell, a transformed cell, a cell from a cancer, or a test organism; administering said treatment to said cell (or test organism) and evaluating the expression of one or more FGF genes, e.g., by contacting a sample from said cell (or test organism) with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF gene products; wherein a change, e.g., decrease, in the level of said one or more FGF genes or gene products in a sample given said treatment, e.g., relative to the level of expression without the treatment, indicative of the effectiveness of the compound for treating said disorder.
- a change e.g., decrease
- the FGF genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
- an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element, e.g., promoter.
- a signal entity e.g., a green fluorescent protein or other marker protein
- an FGF gene control element e.g., promoter.
- nucleic acid (or protein) from the cell or sample is analyzed on positional a ⁇ ays, e.g., DNA-chip a ⁇ ays.
- the method further includes: analyzing the sample by providing an a ⁇ ay of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product; hybridizing the sample with the a ⁇ ay of capture probes, thereby analyzing the sample sequence.
- a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product
- Figure 1 depicts a panel of graphs showing the induction of resistance to paclitaxel, doxorubicin and 5-fluorouracil in monolayer cultures of rat MAT-LyLu tumor cells using conditioned medium (CM) collected from tumor cultures.
- CM conditioned medium
- the induction of drug resistance was detected as changes in proliferative activity by measuring the bromodeoxyuridine (BrdU) inco ⁇ oration in treated samples relative to controls.
- Top panels CM of primary tumors.
- Middle panels CM of lymph node metastases.
- Bottom panels CM of lung metastases.
- Figures 2A-2B depict a panel of graphs showing the reversal of CM-induced resistance by inhibiting or removing aFGF/bFGF.
- Figure 2 A shows the reversal of CM-induced resistance (detected as changes in proliferative activity of rat MAT-LyLu cells by measuring the changes in BrdU inco ⁇ oration in treated samples relative to control samples) using a monoclonal antibody against aFGF or bFGF as indicated.
- the source of CM was lung histocultures for the aFGF experiment, and early monolayer lung cultures for the bFGF experiment.
- Figure 2B shows (a) the reversal of the CM-induced resistance to doxorubicin by removing aFGF and/or bFGF via immunoprecipitation, and (b) the restoration of the resistance by reconstituting the FGF-immunoprecipitated CM using human recombinant proteins (0.16 ng/ml r-aFGF and/or 0.9 ng/ml r-bFGF).
- the study was performed using rat MAT-LyLu cells.
- the reversal in CM-induced resistance was detected by measuring the changes in BrdU inco ⁇ oration in treated samples relative to control samples.
- the source of CM was lung histocultures for both aFGF and bFGF experiments.
- CM minus aFGF and bFGF filled square, overlaps with left control curve
- CM minus aFGF and bFGF plus r-bFGF filled circle
- Lower right CM minus aFGF and bFGF (filled square, overlaps with left control curve); CM minus aFGF and bFGF plus r-aFGF and r-bFGF (filled circle, overlaps with the right CM-control curve).
- Figure 3 is a panel of graphs showing induction of resistance to paclitaxel, doxorubicin and 5-fluorouracil in human prostate PC3 tumor cells using r-aFGF alone, r-bFGF alone or a combination of r-aFGF and r-bFGF, in the absence of CM.
- the study was performed using human prostate PC3 tumor cells (shown here) and rat MAT- LyLu tumor cells.
- the induction of resistance by FGF was detected by measuring the changes in BrdU inco ⁇ oration in treated samples relative to control samples.
- the study used two controls: no CM (left solid curves, empty circles); with CM of lung histocultures (right solid curves, open squares).
- Top panels addition of r-aFGF: 1 (filled circle), 10 (filled square) and 50 (filled inverted triangle) ng/ml. All three dotted curves overlap with the left control curve.
- Middle panels addition of r-bFGF. Dotted curves from left to right: 1 (filled circle, overlaps with the left control curve), 10 (filled square) and 50 (filled inverted triangle, overlaps with the right CM-control curve) ng/ml.
- Bottom panels addition of r-aFGF/r-bFGF combinations.
- Dotted curves from left to right 0.04 and 1 ng/ml (filled square, overlaps with the left control curve); 0.08 and 1 ng/ml (open diamond); 0.16 and 1 ng/ml (filled inverted triangle); 0.32 and 1 ng/ml (filled diamond); 0.64 and 1 ng/ml (filled circle); and 1 ng/ml each (open inverted triangle). Similar results were obtained for rat MAT-LyLu tumor cells.
- Figure is a graph depicting the FGF-induced resistance to cell kill caused by doxorubicin treatment.
- Drug-induced cell death in PC3 cells was monitored by the release of lactate dehydrogenase (LDH) to the culture medium. Results are expressed as a ratio of treated samples to untreated controls. Values for control samples varied by less than 10%.
- LDH lactate dehydrogenase
- Curves from top to bottom Without CM or FGF (open circle); addition of 0.9 ng/ml aFGF (filled inverted triangle, overlaps with top control curve); addition of 0.9 ng/ml bFGF (filled circle); addition of 0.16 ng/ml aFGF plus 0.9 ng/ml bFGF (filled diamond); CM of lung tumor histocultures (open square); 0.9 ng/ml aFGF plus 0.9 ng/ml bFGF (filled square). Similar results were found for paclitaxel, and 5- fluorouracil.
- Figure 5 shows three graphs depicting the cytotoxicity of increasing concentrations of suramin in rat MAT-LyLu tumor cells, human prostate PC3 and PC3- LN tumor cells. These results show that suramin did not produce measurable cytotoxicity (i.e., ⁇ 10% reduction in BrdU inco ⁇ oration) at the 1-15 micromolar concentration.
- the co ⁇ esponding IC 5 o values i.e., suramin concentration required to result in 50% reduction in BrdU inco ⁇ oration
- Figure 6 shows three graphs depicting the enhancement of the cytotoxicity of doxorubicin, paclitaxel and 5-fluorouracil using suramin, under in vitro conditions.
- the study was performed using rat MAT-LyLu tumor cells (shown here) and human prostate PC3 and PC3-LN tumor cells.
- the cytotoxic effect was detected by measuring the changes in BrdU inco ⁇ oration in treated samples relative to control samples.
- the study used two controls: no CM and no suramin (left solid curves, open circle); with CM of lung histocultures but no suramin (right solid curves, open square). Dotted curves from right to left, addition of suramin 5 ⁇ M (filled circle); 10 ⁇ M (filled square); and 15 ⁇ M (filled inverted triangle). Similar results were obtained for PC3 and PC3-LN cells.
- Figures 7A-7B are two graphs depicting the suramin-mediated enhancement of doxorubicin activity in immunodeficient mice bearing subcutaneous bulky human prostate PC3 xenograft tumors.
- Figure 7 A shows the changes in tumor weight (depicted as experimental weight relative to initial weight) with respect to duration of treatment.
- Figure 7B shows the changes in the animal body weight with respect to duration of treatment.
- the present invention is based, at least in part, on the discovery that bFGF induces broad spectrum resistance to anticancer agents, in a number of solid and soft- tissue tumors, metastatic lesions, as well as normal noncancerous intestinal epithelium.
- the bFGF-induced resistance was amplified by aFGF.
- the invention shows that inhibitors of aFGF/bFGF enhanced the in vitro and in vivo activity of chemotherapy, resulting in shrinkage and eradication of well-established human lung metastasis and human subcutaneous xenograft tumors in mice. Accordingly, the present invention provides, in part, methods and compositions for inhibiting FGF- induced resistance to anticancer agents.
- the FGF inhibitor is administered with other cytotoxic agents, e.g., an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti- hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
- cytotoxic agents e.g., an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g.,
- the enhanced, and sometimes synergistic, effect of the FGF inhibitors) e.g., suramin, e.g., FGF antibody
- anticancer agents e.g., paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, Herceptin, anti- CD20, leuprolide (Lupron) and flutamide
- FGF inhibitors e.g., suramin, e.g., FGF antibody
- anticancer agents e.g., paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT,
- the subject is a patient with non-small cell lung cancer, who is treated with a combination of paclitaxel, carboplatin and suramin, or with a combination of gemcitabine, cisplatin, and suramin.
- the patient is a patient with hormone refractory prostate cancer, who is treated with a combination of estramustine phosphate, taxotere and suramin, or with a combination of doxorubicin, ketoconazole and suramin.
- the patient is a patient with metastatic breast cancer, who is treated with a combination of cyclophosphamide, doxorubicin, 5- fluorouracil and suramin.
- the patient is a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with a Her2/neu antibody (e.g., Herceptin) and suramin, with or without paclitaxel or cisplatin.
- a Her2/neu antibody e.g., Herceptin
- suramin e.g., paclitaxel or cisplatin.
- the patient is a patient with advanced or metastatic colorectal cancer, who is treated with a combination of irinotecan and suramin.
- the patient is a patient with advanced colon cancer, who is treated with a combination of 5- fluorouracil, leucovorin and suramin.
- CM conditioned medium
- solid, soft-tissue tumors, and metastatic tumors induced resistance to multiple anticancer agents, in human and rodent tumor cells.
- CM contained elevated levels of aFGF and bFGF (see Examples II- III).
- Inhibition of bFGF using a bFGF-specific monoclonal antibody and removal of bFGF by immunoprecipitation resulted in complete reversal of the CM-induced resistance to anticancer agents, whereas inhibition/removal of aFGF resulted in partial reversal (see Example IV).
- CM that had been depleted of aFGF and/or bFGF and subsequently reconstituted with respective human recombinant proteins
- bFGF but not aFGF was found to induce resistance.
- aFGF was found to amplify the bFGF effect.
- aFGF and bFGF fully accounted for the CM effect, indicating these proteins are involved in the induction and maintenance of resistance to anticancer agents (see Example IV).
- the FGF-induced resistance was not due to reduced intracellular drug accumulation, nor altered cell proliferation (see Example XII), thus representing a novel epigenetic resistance mechanism.
- aFGF and bFGF as found in the active CM, induced broad spectrum resistance to at least 58 anticancer agents having different mechanisms of actions, including antitubulin/antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, alkylating agents, intercalating agents, agents that interfere with signal transduction pathways (e.g., protein kinase C inhibitors), and agents that promote apoptosis and/or necrosis (see Examples II and VII).
- anticancer agents having different mechanisms of actions, including antitubulin/antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, alkylating agents, intercalating agents, agents that interfere with signal transduction pathways (e.g., protein kinase C inhibitors), and agents that promote apoptosis and/or necrosis (see Examples II and VII).
- aFGF/bFGF induction of resistance to paclitaxel an antimicrotubule agent
- doxorubicin a topoisomerase I inhibitor
- 5-fluorouracil an antimetabolite
- inhibitors of FGF including FGF antibodies and suramin, an inhibitor of multiple growth factors, including aFGF/bFGF, reverse the FGF-induced resistance and enhance the in vitro activity of anticancer agents, including at least 58 anticancer agents having different mechanisms of actions, including antitubulin antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, alkylating agents, intercalating agents, agents that interfere with signal transduction pathways (e.g., protein kinase C inhibitors), and agents that promote apoptosis and/or necrosis (see Examples V and VII).
- anticancer agents including antitubulin antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, alkylating agents, intercalating agents, agents that interfere with signal transduction pathways (e.g., protein kinase C inhibitors), and agents that promote apoptosis and/or necrosis (
- the appended examples further demonstrate that (a) presence of tumor cells enhanced the level of extracellular bFGF in host tissues, (b) bFGF level in tumors is determined by the location and the size of the tumor, and (c) bFGF level determines the sensitivity of human patient tumors to anticancer agents (see Example X).
- the appended examples show that treatment of human prostate cells with several anticancer agents with diverse structures and action mechanisms (e.g., antitubulin/antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, alkylating agents, and antimetabohtes) significantly enhanced the level of extracellular bFGF (see Example XI).
- these examples indicate (a) the use of FGF gene expression and level to detect the presence of tumor cells, (b) the use of FGF expression and level in tumors to determine the extent of resistance, (c) the use of FGF gene expression and level in tumors to determine the dosage of the FGF inhibitors, and (d) that patients that are previously treated with chemotherapy are likely to exhibit chemoresistance. The latter indicates the need of using FGF inhibitors to treat patients who have failed cancer therapy and have recurrent tumors.
- FGF antagonists e.g., suramin, e.g., heparin, e.g., low molecular weight heparin, e.g., heparan sulfate
- FGF antagonists e.g., suramin, e.g., heparin, e.g., low molecular weight heparin, e.g., heparan sulfate
- FGF agonists e.g., aFGF, bFGF
- anticancer agents e.g., paclitaxel and doxorubicin
- the invention also provides methods and compositions for treating or preventing the undesired host toxicity of anticancer agents using aFGF and bFGF, alone or in combination.
- the findings described herein demonstrate, inter alia, (a) a novel epigenetic mechanism by which cancer cells utilize the unique microenvironment of solid tumors and metastases to elude cytotoxic insult, (b) an important role of extracellular growth factors in tumor sensitivity to anticancer agents, (c) a new cancer treatment paradigm using combinations of anticancer agents with aFGF/bFGF inhibitors, (d) a novel mechanism and methods by which normal noncancerous host cells can be protected from the undesired toxicity of anticancer agents, and (e) methods to use the bFGF level for making therapeutic decision for individual patients.
- fibroblast growth factor refers to a member of a family of polypeptides that are potent regulators of a variety of cellular processes including proliferation, differentiation, migration, mo ⁇ hogenesis, tissue maintenance and in wound healing and repair (Clarke et al. (1993) J. Cell Sci.106: 121-133; Cuevas et al. (1988) Biochem. Biophys. Res. Commun. 156: 611-618; Burgess, W.H. and Maciag, T (1989) Ann. Rev. Biochem. 58: 575-606; Rifkin, D.B.
- FGF fibroblast growth factor
- the FGF family cu ⁇ ently includes at least 19 structurally and functionally related proteins, including acidic and basic FGF, FGF-1 and FGF-2 respectively; int2 (FGF-3); hst (FGF-4); FGF-5; hst2 (FGF-6); keratinocyte growth factor (FGF-7); androgen-induced growth factor (FGF-8); glia-activating factor (FGF- 9); FGF-10-19 (Galzie, Z. et al. (1997) Biochem. Cell. Biol., 75:669-685; Yamasaki, M. et al. (1996) J. Biol.
- FGF refers to acidic and basic FGF, FGF-1 and FGF-2, respectively (reviewed in (Galzie, Z. et al. (1997) Biochem. Cell. Biol., 75:669-685 and Burgess, W.H. and Maciag, T (1989) Ann. Rev. Biochem. 58: 575-606).
- FGF receptor refers to FGF -binding polypeptides that possess intrinsic tyrosine kinase activity or heparan sulfate proteoglycans in the extracellular matrix.
- tyrosine kinase receptors there are cu ⁇ ently four known genes encoding FGF receptors (FGFR-1, FGFR-2, FGFR-3, and FGFR-4), which can give rise to a variety of protein isoforms via alternative RNA splicing (Galzie, Z. et al. (1997) Biochem. Cell. Biol., 75:669-685).
- the structure of the FGFR consists of an extracellular region with three immunoglobulin-like domains, a transmembrane region, and a cytosolic tyrosine kinase domain that is activated upon ligand binding. FGF binding causes dimerization of the receptors, resulting in receptor autophosphorylation on tyrosine residues and the activation of intracellular signal transduction cascades.
- the term "FGFR” also includes heparan sulfate proteoglycans in the extracellular matrix which mediate the actions of FGF, e.g., protection from proteolysis, localization, storage, and internalization of growth factors (Faham, S. et al. (1998) Curr. Opin. Struct.
- Heparan sulfate proteoglycans may serve as low affinity FGF receptors that act to present FGF to its cognate FGFR, and/or to facilitate receptor oligomerization (Galzie, Z. et al. (1997) Biochem. Cell. Biol, 75:669-685).
- an "FGF antagonist" refers to an agent that inhibits (completely or partially) the activity, production, stability, of an FGF molecule.
- the FGF antagonist acts extracellularly or intracellularly, e.g., inhibits the binding of an FGF molecule to an extracellular or intracellular domain of an FGF receptor, e.g., blocks the intracellular signalling initiated by activation of the FGF receptor.
- the inhibitor binds to the intracellular domain of the FGF receptor, or blocks a downstream action that is consequence of activation of the FGF receptor.
- an "FGF agonist” refers to an agent that potentiates the activity, production, stability, of an FGF molecule, or activates FGF receptors.
- telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomere telomeres As used herein, the term “specific inhibitor of FGF” refers to an FGF antagonist other than suramin.
- cytotoxic agent As used herein, the terms “cytotoxic agent”, “anticancer agent” and “antitumor agent” are used interchangeably herein and refer to agents that have the property of inhibiting the growth or proliferation (e.g., a cytostatic agent), or inducing the killing, of hype ⁇ roliferative cells.
- the cytotoxic agent inhibits or reverses the development or progression of a neoplasm, such as a solid tumor, a soft tissue tumor, a metastatic lesion, a lymphoma, or a leukemia, or the cytotoxic agent inhibits or reverses the development or progression of a benign hype ⁇ lastic growth.
- a "therapeutically effective amount" of an FGF antagonist and a cytotoxic agent refers to an amount of such agents which in combination is effective, upon single- or multiple-dose administration to the subject, e.g., a patient, at inhibiting the growth or proliferation, or inducing the killing, of hype ⁇ roliferative cells.
- Such growth inhibition or killing can be reflected as a prolongation of the survival of the subject, e.g., a patient beyond that expected in the absence of such treatment, or any improvement in the prognosis of the subject relative to the absence of such treatment.
- the phrase refers to an amount of such agent which is effective, upon single- or multiple-dose administration to protect a cell in a subject, e.g., a patient, from damage by an agent, e.g., a cytotoxic agent.
- a prophylactically effective amount of an FGF antagonist and a cytotoxic agent refers to an amount of such agents which in combination is effective, upon single or multiple dose administration to the subject, e.g., a patient, in preventing or delaying the occu ⁇ ence of the onset or recu ⁇ ence of a neoplastic disease state.
- the phrase refers to an amount of such agent which is effective, upon single- or multiple-dose administration, in preventing or delaying damage to a cell in a subject, e.g., a patient, by an agent, e.g., a cytotoxic agent.
- the language "subject” is intended to include human and non- human animals.
- Prefe ⁇ ed human animals include a human patient having a disorder characterized by the abe ⁇ ant activity of a hype ⁇ roliferative cell.
- the term "non- human animals” of the invention includes all vertebrates, e.g., mammals and non- mammals, such as non-human primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, etc.
- the subject is a human patient, e.g., a cancer patient, e.g., a patient with a benign hype ⁇ lastic disorder.
- neoplastic cell e.g., benign hype ⁇ lastic cell
- inhibiting the growth or proliferation of the hype ⁇ roliferative cell refers to slowing, interrupting, a ⁇ esting or stopping its growth and metastasis, and does not necessarily indicate a total elimination of the neoplastic growth.
- inducing the killing of the hype ⁇ roliferative cell refers to the partial or complete elimination of such cells, and does not necessarily indicate a total elimination of the neoplastic growth.
- hypo ⁇ roliferative As used herein, the terms “hype ⁇ roliferative”, “hype ⁇ lastic”, “malignant”, and “neoplastic” are used interchangeably, and refer to those cells in an abnormal state or condition characterized by rapid proliferation or neoplasm. The terms are meant to include all types of hype ⁇ roliferative growth, hype ⁇ lastic growth, cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, i ⁇ espective of histopathologic type or stage of invasiveness. "Pathologic hype ⁇ roliferative" cells occur in disease states characterized by malignant tumor growth or in disease states characterized by benign hype ⁇ roliferative and hype ⁇ lastic cells.
- Neoplasia refers to "new cell growth” that results as a loss of responsiveness to normal growth controls, e.g., neoplastic cell growth.
- a “hype ⁇ lasia” refers to cells undergoing an abnormally high rate of growth.
- neoplasia and hype ⁇ lasia can be used interchangeably, as their context will reveal, referring generally to cells experiencing abnormal cell growth rates.
- Neoplasias and hype ⁇ lasias include “tumors,” which may be either benign, premalignant or malignant.
- carcinoma is recognized by those skilled in the art and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
- Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary.
- carcinosarcomas e.g., which include malignant tumors composed of carcinomatous and sarcomatous tissues.
- An "adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
- leukemia or leukemic cancer refers to all cancers or neoplasias of the hemopoietic and immune systems (blood and lymphatic system). These terms refer to a progressive, malignant disease of the blood-forming organs, marked by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
- Myelolomas refer to other types of tumors of the blood, bone ma ⁇ ow cells.
- Lymphomas refer to tumors of the lymph tissue.
- immunoglobuhn and “antibody” refer to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, a ⁇ anged from amino-terminus to carboxy-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies may mediate the binding of the immunoglobuhn to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a target antigen).
- binding fragments encompassed within the term “antigen-binding portion” of an antibody include (a) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (b) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (c) a Fd fragment consisting of the VH and CHI domains; (d) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (e) a dAb fragment (Ward et al, (1989) Nature 341:544-546), which consists of a VH domain; and (f) an isolated complementarity determining region (
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl Acad. Sci. USA 85:5879-5883).
- single chain Fv single chain Fv
- Such single chain antibodies are encompassed within the term "antigen-binding portion" of an antibody.
- the term "monoclonal antibody” as used herein refers to an antibody molecule of single molecular composition.
- a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- the term “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobuhn sequences.
- the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
- recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobuhn genes; antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobuhn gene sequences to other DNA sequences.
- Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobuhn sequences.
- such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
- this invention features methods for inhibiting the proliferation, and/or enhancing the killing of, hype ⁇ roliferative cells, by contacting the cells with at least one cytotoxic agent and at least one FGF antagonist.
- the method includes a step of contacting pathological hype ⁇ roliferative cells with an amount of at least one cytotoxic agent and at least one FGF antagonist, which, in combination, is effective to reduce or inhibit the proliferation of the cell, or induce cell killing.
- the present method can be performed on cells in culture, e.g., in vitro or ex vivo, or can be performed on cells present in a subject, e.g., as part of an in vivo therapeutic protocol.
- the therapeutic regimen can be carried out on a human or on other animal subjects.
- the enhanced therapeutic effectiveness of the combination therapy of the present invention represents a promising alternative to conventional highly toxic regimens of anticancer agents.
- the subject methods are preferably combined with other anticancer agents, e.g., antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabohtes, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), agents that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
- a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
- agents that promotes apoptosis and/or necrosis e.g., an interferon, an interleukin, a tumor necrosis factor
- the enhanced, and sometimes synergistic, effect of the FGF inhibitor(s) e.g., suramin, e.g., FGF antibody
- anticancer agents e.g., paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, Herceptin, anti- CD20, leuprolide (Lupron) and flutamide), in addition to improving the efficacy of these anticancer agents, may allow for the administration of lower doses of these anticancer agents, thus reducing the induction of side effects in a subject.
- FGF inhibitor(s) e.g., suramin, e.g., FGF antibody
- anticancer agents e.g., paclitaxel, interferon alpha,
- the subject method can be useful in treating malignancies of the various organ systems, such as those affecting lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary tract (e.g., prostate), pharynx, as well as adenocarcinomas which include malignancies such as most colon cancer, rectal cancer, renal cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
- malignancies of the various organ systems such as those affecting lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary tract (e.g., prostate), pharynx, as well as adenocarcinomas which include malignancies such as most colon cancer, rectal cancer, renal cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
- Exemplary solid tumors that can be treated include: fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,
- the subject method may also be used to inhibit the proliferation or induce the killing of hype ⁇ lastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof.
- the present invention contemplates the treatment of various myeloid disorders including, but not limited to, acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus, L. (1991) Crit. Rev. Oncol/Hemotol. 11:267-97).
- APML acute promyeloid leukemia
- AML acute myelogenous leukemia
- CML chronic myelogenous leukemia
- Lymphoid malignancies which may be treated by the subject method include, but are not limited to acute lymphoblastic leukemia (ALL), which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and
- ALL acute lymphoblastic leukemia
- CLL chronic lymphocytic leukemia
- PLL prolymphocytic leukemia
- HLL hairy cell leukemia
- WM Waldenstrom's macroglobulinemia
- Additional forms of malignant lymphomas contemplated by the treatment method of the present invention include, but are not limited to, non-Hodgkin's lymphoma and variants thereof, peripheral T-cell lymphomas, adult T-cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF) and Hodgkin's disease.
- the subject method may also be used to inhibit the proliferation or induce the killing of benign hype ⁇ lastic growth.
- FGF antagonists are also be used to inhibit the proliferation or induce the killing of benign hype ⁇ lastic growth.
- the FGF antagonist used in the methods and compositions of the present invention can be a chemical, e.g., a protein or a peptide, or a small molecule.
- the FGF antagonist is an inhibitor of bFGF, aFGF, or an inhibitor of both.
- the FGF antagonist can be capable of binding to an FGF molecule, a molecule that facilitates the binding of FGF to a receptor, or an FGF receptor and, thereby, blocking the binding of an FGF molecule to a receptor (e.g., a tyrosine kinase receptor and/or a heparan sulfate proteoglycan).
- the FGF antagonist may also down regulate FGF receptor action, e.g., blocks the intracellular signalling initiated by activation of the FGF receptor.
- the inhibitor binds to the intracellular domain of the FGF receptor, or blocks a downstream action that is consequence of activation of the FGF receptor.
- Examples of chemicals that may antagonize FGF action include suramin, structural analogs of suramin, pentosan polysulfate, scopolamine, angiostatin, sprouty, estradiol, carboxymethylbenzylamme dextran (CMDB7), suradista, insulin-like growth factor binding protein-3, ethanol, heparin (e.g., 6-O-desulfated heparin), low molecular weight heparin, protamine sulfate, cyclosporin A, or RNA ligands for bFGF.
- the FGF antagonist may also be a small molecule, e.g., a member of a combinatorial library.
- a prefe ⁇ ed FGF antagonist is suramin.
- suramin is present in a concentration sufficient to block the resistance to anticancer agents induced by FGF (e.g., bFGF and/or aFGF), but is not sufficient to produce significant cytotoxicity (e.g., significant inhibition of cell proliferation, e.g., significant cell death) in human and/or animal tumor cells, not sufficient to cause significant cell cycle a ⁇ est, and/or not sufficient to produce measurable antitumor effect in a subject, e.g., a human subject.
- FGF e.g., bFGF and/or aFGF
- suramin is administered in an amount that results in a plasma concentration ranging from about 0.1 to 100 microgram/ml, preferably about 1 to 85 microgram/ml, more preferably, about 5 to 60 microgram/ml, even more preferably, about 10 to 50 microgram/ml, and most preferably, 15 to 45 microgram/ml, of the plasma concentration.
- proteins or peptide that may antagonize FGF activity include antibodies, e.g., a monoclonal antibody or an antigen fragment thereof, as described below.
- the FGF antagonist is a fragment of the FGF molecule.
- the FGF fragment competes with an FGF molecule for binding to the receptor.
- the FGF antagonist may also be transforming growth factor beta or a fragment thereof.
- proteins or peptide that may antagonize FGF activity include antibodies, e.g., a monoclonal antibody, a murine antibody or a human antibody, or an antigen-binding fragment thereof.
- the monoclonal antibody is a human antibody.
- the human antibody can be produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
- the antibodies can be of the various isotypes, including: IgG (e.g., IgGl, IgG2, IgG3, IgG4), IgM, IgNl, IgA2, IgD, of IgE.
- the antibody is an IgG isotype.
- the antibodies can be full-length (e.g., an IgGl or IgG4 antibody) or can include only an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv or a single chain Fv fragment).
- antibodies against bFGF and FGF are commercially available, and can be readily used in the methods and compositions of the invention.
- Examples of antibodies to bFGF that are commercially available include: (a) Sigma F 9666, anti- human, monoclonal, clone no. FA-88, host: mouse, type:IgG2a; (b) Sigma F 5521, polyclonal, host: rabbit; and (c) Oncogene PC316L, anti-bovine+anti-human, polyclonal, host: rabbit, type IgG.
- antibodies to aFGF examples include: (a) Sigma F 6162, anti-human, monoclonal, clone no. FB-8, host: mouse, type: IgGl; (b) Sigma F 5537, anti-human, polyclonal, host: rabbit, type: IgG; (c) Sigma F 3393, anti- bovine, polyclonal, host: rabbit; (d) Oncogene PC15, anti-human, polyclonal, AB-1, host: rabbit, type: IgG; (e) Oncogene PC 16, anti-human, polyclonal, AB-2, host: rabbit, type: IgG; (f) Oncogene GF22, anti-human, monoclonal, clone no.
- 3H3, AB-3 host: mouse, type: IgGl;
- Oncogene GF23L anti-human, monoclonal, clone no. 98, AB-4, host: mouse, type: IgGl;
- Oncogene GF24 anti-human, monoclonal, clone no. 52, AB-5, host: mouse, type: IgG2b; and
- the anti-FGF antibody can be made by methods known in the art.
- an anti-FGF antibody can be produced by a variety of techniques, including conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein (1975) Nature 256: 495.
- somatic cell hybridization procedures are prefe ⁇ ed, in principle, other techniques for producing monoclonal antibody can be employed, e.g., viral or oncogenic transformation of B lymphocytes.
- the prefe ⁇ ed animal system for preparing hybridomas is the murine system. Hybridoma production in the mouse is a very well- established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art.
- Fusion partners e.g., murine myeloma cells
- Human monoclonal antibodies (mAbs) directed against human proteins can be generated using transgenic mice carrying the complete human immune system rather than the mouse system. Splenocytes from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for epitopes from a human protein (see, e.g., Wood et al. International Application WO 91/00906, Kucherlapati et al. PCT publication WO 91/10741; Lonberg et al. International Application WO 92/03918; Kay et al.
- Monoclonal antibodies can also be generated by other methods known to those skilled in the art of recombinant DNA technology.
- An alternative method, refe ⁇ ed to as the "combinatorial antibody display” method, has been developed to identify and isolate antibody fragments having a particular antigen specificity, and can be utilized to produce monoclonal antibodies (for descriptions of combinatorial antibody display see e.g., Sastry et al. (1989) Proc. Natl. Acad. Sci. USA 86:5728; Huse et al. (1989) Science 246:1275; and Orlandi et al. (1989) Proc. Natl Acad. Sci. USA 86:3833; Larrick et al. (1991), Biotechniques 11 :152-156; Larrick et al (1991), Methods: Companion to Methods in Enzymology 2:106-110).
- RNA is isolated from B lymphocytes, for example, peripheral blood cells, bone ma ⁇ ow, or spleen preparations, using standard protocols (e.g., U.S. Patent No. 4,683,202; Orlandi, et ⁇ /.(1989) Proc. Natl. Acad. Sci. USA 86:3833-3837; Sastry et al. (1989) Proc. Natl Acad. Sci. USA 86:5728-5732; and Huse et al.
- standard protocols e.g., U.S. Patent No. 4,683,202; Orlandi, et ⁇ /.(1989) Proc. Natl. Acad. Sci. USA 86:3833-3837; Sastry et al. (1989) Proc. Natl Acad. Sci. USA 86:5728-5732; and Huse et al.
- First-strand cDNA is synthesized using primers specific for the constant region of the heavy chain(s) and each of the K and ⁇ light chains, as well as primers for the signal sequence.
- variable region PCR primers the variable regions of both heavy and light chains are amplified, each alone or in combination, and ligated into appropriate vectors for further manipulation in generating the display packages.
- Ohgonucleotide primers useful in amplification protocols may be unique or degenerate or inco ⁇ orate inosine at degenerate positions. Restriction endonuclease recognition sequences may also be inco ⁇ orated into the primers to allow for the cloning of the amplified fragment into a vector in a predetermined reading frame for expression.
- the V-gene library cloned from the immunization-derived antibody repertoire can be expressed by a population of display packages, preferably derived from filamentous phage, to form an antibody display library.
- the display package comprises a system that allows the sampling of very large variegated antibody display libraries, rapid sorting after each affinity separation round, and easy isolation of the antibody gene from purified display packages.
- kits for generating phage display libraries e.g., the Pharmacia Recombinant Phage
- the V region domains of heavy and light chains can be expressed on the same polypeptide, joined by a flexible linker to form a single-chain Fv fragment, and the scFV gene subsequently cloned into the desired expression vector or phage genome.
- a flexible linker As generally described in McCafferty et al. (1990) Nature 348:552- 554, complete VH and VL domains of an antibody, joined by a flexible (Gly_ ⁇ -Ser)3 linker can be used to produce a single chain antibody which can render the display package separable based on antigen affinity. Isolated scFV antibodies immunoreactive with the antigen can subsequently be formulated into a pharmaceutical preparation for use in the subject method.
- the antibody library is screened with the target antigen, or peptide fragment thereof, to identify and isolate packages that express an antibody having specificity for the target antigen.
- Nucleic acid encoding the selected antibody can be recovered from the display package (e.g., from the phage genome) and subcloned into other expression vectors by standard recombinant DNA techniques.
- Specific antibody molecules with high affinities for a surface protein can be made according to methods known to those in the art, e.g., methods involving screening of libraries (Ladner, R.C., et al, U.S. Patent 5,233,409; Ladner, R.C., et al, U.S. Patent 5,403,484). Further, the methods of these libraries can be used in screens to obtain binding determinants that are mimetics of the structural determinants of antibodies.
- the Fv binding surface of a particular antibody molecule interacts with its target ligand according to principles of protein-protein interactions, hence sequence data for VH and VL (the latter of which may be of the K or ⁇ chain type) is the basis for protein engineering techniques known to those with skill in the art.
- sequence data for VH and VL is the basis for protein engineering techniques known to those with skill in the art.
- Details of the protein surface that comprises the binding determinants can be obtained from antibody sequence information, by a modeling procedure using previously determined three-dimensional structures from other antibodies obtained from NMR studies or crytallographic data. See for example Bajorath, J. and S. Sheriff, (1996) Proteins: Struct., Fund., and Genet. 24, 152-157; Webster, D.M. and A. R. Rees (1995) "Molecular modeling of antibody-combining sites" in S.
- a variegated peptide library is expressed by a population of display packages to form a peptide display library.
- the display package comprises a system that allows the sampling of very large variegated peptide display libraries, rapid sorting after each affinity separation round, and easy isolation of the peptide-encoding gene from purified display packages.
- Peptide display libraries can be in, e.g., prokaryotic organisms and viruses, which can be amplified quickly, are relatively easy to manipulate, and which allows the creation of large number of clones.
- Prefe ⁇ ed display packages include, for example, vegetative bacterial cells, bacterial spores, and most preferably, bacterial viruses (especially DNA viruses).
- modified or “recombinant” antibody is also intended to include antibodies, such as monoclonal antibodies, chimeric antibodies, and humanized antibodies which have been modified by, e.g., deleting, adding, or substituting portions of the antibody.
- an antibody can be modified by deleting the hinge region, thus generating a monovalent antibody. Any modification is within the scope of the invention so long as the antibody has at least one antigen binding region specific.
- Chimeric mouse-human monoclonal antibodies can be produced by recombinant DNA techniques known in the art (see Robinson et al, International Patent Publication PCT/US86/02269; Akira, et al, European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al, European Patent Application 173,494; Neuberger et al, International Application WO 86/01533; Cabilly et al. U.S. Patent No. 4,816,567; Cabilly et al, European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043); Liu et al.
- the chimeric antibody can be further humanized by replacing sequences of the Fv variable region which are not directly involved in antigen binding with equivalent sequences from human Fv variable regions.
- General reviews of humanized chimeric antibodies are provided by Morrison, S. L. (1985) Science 229:1202-1207 and by Oi et al. (1986) BioTechniques 4:214. Those methods include isolating, manipulating, and expressing the nucleic acid sequences that encode all or part of immunoglobuhn Fv variable regions from at least one of a heavy or light chain. Sources of such nucleic acid are well known to those skilled in the art and, for example, may be obtained from 7E3, an anti-GPIIi,III a antibody producing hybridoma.
- Suitable humanized antibodies can alternatively be produced by CDR substitution U.S. Patent 5,225,539; Jones et al. (1986) Nature 321 :552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141 :4053-4060.
- All of the CDRs of a particular human antibody may be replaced with at least a portion of a non-human CDR or only some of the CDRs may be replaced with non- human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to the Fc receptor.
- An antibody can be humanized by any method, which is capable of replacing at least a portion of a CDR of a human antibody with a CDR derived from a non-human antibody.
- Winter describes a method which may be used to prepare the humanized antibodies of the present invention (UK Patent Application GB 2188638A).
- the human CDRs may be replaced with non-human CDRs using ohgonucleotide site- directed mutagenesis.
- chimeric and humanized antibodies in which specific amino acids have been substituted, deleted or added.
- prefe ⁇ ed humanized antibodies have amino acid substitutions in the framework region, such as to improve binding to the antigen.
- amino acids located in the human framework region can be replaced with the amino acids located at the co ⁇ esponding positions in the mouse antibody. Such substitutions are known to improve binding of humanized antibodies to the antigen in some instances.
- Antibodies in which amino acids have been added, deleted, or substituted are refe ⁇ ed to herein as modified antibodies or altered antibodies. Cytotoxic Agents
- the FGF antagonist is preferably administered in combination with at least one cytotoxic agent.
- the term "in combination" in this context means that the agents are given substantially contemporaneously, either simultaneously or sequentially. If given sequentially, at the onset of administration of the second compound, the first of the two compounds is preferably still detectable at effective concentrations at the site where treatment effect is desired.
- the FGF antagonists can be used in combination therapy with conventional cancer chemotherapeutics.
- Conventional treatment regimens for leukemia and for other tumors include radiation, antitumor agents, interferons, interleukins, tumor necrosis factors, or a combination of two or more of these agents.
- the subject method may involve, in addition to the use of at least one FGF inhibitor, one or more other antitumor agents.
- exemplary combination therapies include the use of such agents as, e.g., the ones described in Table 2 below, including but not limited to: antitubulin/antimicrotubule agents, e.g., paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel); topoisomerase I inhibitors, e.g., topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar); topoisomerase II inhibitors, e.g., doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride; antimetabohtes
- Examples of additional agents that can be used in combination with the FGF inhibitors include hydroxyurea, azathioprine, aminopterin, trimethoprin, pyrimethamine, pyritrexim, DDMP (2,4 diamino- 5(3',4' dichlorophenyl)6 methylpyrimidine), 5,10- dideazatetrahydrofolate,10-propargyl-5,8 dideazafolate (CB3717), 10-ethyl-lO-deaza- aminopterin, deoxycytidine, 5-aza-cytosine arabinoside, N-4-palmitoyl-ara C, 2'-azido-2'- deoxy-ara C, N4-behenoyl-ara C, CCNU (lomustine), estramustine, MeCCNU, triethylene melamine, trenimon, dimethyl busulfan, streptozotocin, chlorozotocin, procarbazine, hexamethylmelamine (
- cytotoxic agents can be used depending on the type of hype ⁇ roliferative disorder to be treated.
- the following drugs usually in combinations with each other, are often used to treat acute leukemias: vincristine, prednisone, methotrexate, mercaptopurine, cyclophosphamide, and cytarabine.
- chronic leukemia for example, fludarabine, busulfan, melphalan, and chlorambucil can be used in combination.
- paclitaxel and carboplatin or a combination of gemcitabine and cisplatin is used.
- a combination of estramustine phosphate and taxotere or a combination of doxorubicin and ketoconazole is used.
- a combination of cyclophosphamide, doxorubicin and 5-fluorouracil is used.
- an anti-Her2/neu antibody e.g., Herceptin
- cisplatin is used.
- 5-fluorouracil and leucovorin is used.
- Cytotoxic agents are also used to treat benign hype ⁇ lasia disorders. For example, psoriasis is treated with 5-fluorouracil. Treatment can be initiated with smaller dosages that are less than the optimum dose of the agent. Thereafter, the dosage should be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
- a therapeutically effective antitumor amount and a prophylactically effective antitumor amount of an FGF inhibitor or a cytotoxic agent is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day.
- Determination of a therapeutically effective antitumor amount and a prophylactically effective antitumor amount of a FGF inhibitor and cytotoxic agent can be readily made by the physician or veterinarian (the "attending clinician").
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the particular agent being employed.
- a number of factors are considered by the attending clinician, including, but not limited to: the specific hype ⁇ lastic/neoplastic cell involved; pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concu ⁇ ent treatment; and other relevant circumstances.
- the present invention shows that the bFGF level determines the tumor sensitivity to anticancer agents, thus indicating the use of bFGF level in tumors for therapeutic decision making, including the selection of a therapeutic modality, e.g., a particular anticancer treatment , or a dosage thereof, based on the level of FGF expression.
- a therapeutic modality e.g., a particular anticancer treatment
- a dosage thereof based on the level of FGF expression.
- kits for carrying out the combined administration of the FGF antagonist/agonist with other therapeutic compounds comprises an FGF antagonist/agonist formulated in a pharmaceutical carrier, and at least one cytotoxic agent, formulated as appropriate, in one or more separate pharmaceutical preparations.
- compositions which comprise a therapeutically-effective amount of at least one FGF antagonist/agonist, formulated together with or without at least one cytotoxic agent, in a pharmaceutically acceptable carrier(s).
- the pharmaceutical compositions of the invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (a) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes, mouthwash, hydrogels; (b) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (c) intracavity administration, e.g., intraperitoneal instillation, intravesical (i.e., urinary bladder) instillation, intrathecal administration, (d) intraorgan administration, e.g., intraprostatical administration, (e) topical application, for example, as a cream, ointment or spray applied to the skin; (f) intravaginal or intrarectal administration, for example, as a pessary, cream, foam
- FGF antagonist/agonist can be administered to the subject prior to, simultaneously with, or after the administration of the other cytotoxic agent(s). Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation.
- phrases "pharmaceutically acceptable” is employed herein to refer to those FGF antagonist/agonist and/or cytotoxic agent, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
- a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- materials which can serve as pharmaceutically-acceptable carriers include: (a) sugars, such as lactose, glucose and sucrose; (b) starches, such as com starch and potato starch; (c) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (d) powdered tragacanth; (e) malt; (f) gelatin; (g) talc; (h) excipients, such as cocoa butter and suppository waxes; (i) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (j) glycols, such as propylene glycol; (k) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (1) esters, such as ethyl oleate and ethyl laurate; (m) agar; (
- wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- antioxidants examples include: (a) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (b) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (c) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluen
- compositions containing the FGF antagonist/agonist and/or cytotoxic agent of the present invention may conveniently be presented in unit dosage form.
- the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. Generally, out of one hundred per cent, this dosage will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
- compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, hydrogels, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and/or as mouthwashes and the like, each containing a predetermined amount of a FGF antagonist/agonist and/or cytotoxic agent as an active ingredient.
- a compound may also be administered as a bolus, electuary or paste.
- solid dosage forms of the invention for oral administration capsules, tablets, pills, dragees, powders, granules, hydrogels and the like
- the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate.
- the pharmaceutical compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, nanoparticles, hydrogels, and/or microspheres.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of the FGF antagonist/agonist and/or cytotoxic agent of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art, such as, for example, water
- Suspensions in addition to the active FGF antagonist/agonist and/or cytotoxic agent may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more FGF antagonist/agonist and/or cytotoxic agent with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
- suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
- compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration of a FGF antagonist/agonist and/or cytotoxic agent include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active FGF antagonist/agonist and/or cytotoxic agent may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- the ointments, pastes, creams and gels may contain, in addition to FGF antagonist/agonist and/or cytotoxic agent, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- the FGF antagonist/agonist and/or cytotoxic agent can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are prefe ⁇ ed because they minimize exposing the agent to shear, which can result in degradation of the compound. Transdermal patches have the added advantage of providing controlled delivery of a FGF antagonist/agonist and/or cytotoxic agent to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.
- compositions of this invention suitable for parenteral and/or intracavity administration comprise one or more FGF antagonist/agonist and/or cytotoxic agent in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- the abso ⁇ tion of the drug in order to prolong the effect of a drug, it is desirable to slow the abso ⁇ tion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material having poor water solubility. The rate of abso ⁇ tion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed abso ⁇ tion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
- Injectable or implantable depot forms are made by forming matrices (e.g., microcapsules, e.g., cylinders, e.g., discs) of FGF antagonist/agonist and/or cytotoxic agent in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
- matrices e.g., microcapsules, e.g., cylinders, e.g., discs
- biodegradable polymers such as polylactide-polyglycolide.
- examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot
- Depot formulations can also be administered directly to tumor-bearing organs and/or cavity, e.g., urinary bladder, e.g., intraperitoneal cavity, e.g., intrathecally to brain tissue, to achieve localized delivery of FGF antagonist/agonist and/or cytotoxic agent.
- tumor-bearing organs and/or cavity e.g., urinary bladder, e.g., intraperitoneal cavity, e.g., intrathecally to brain tissue, to achieve localized delivery of FGF antagonist/agonist and/or cytotoxic agent.
- administration is intended to include routes of introducing to a subject of the FGF antagonist/agonist and/or cytotoxic agent to perform their intended function.
- routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecally, etc.), intravesically (i.e., urinary bladder), intraprostatically, oral, inhalation, rectal and transdermal.
- the pharmaceutical preparations are of course given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc.
- the injection can be bolus or can be bycontinuous infusion.
- the FGF antagonist/agonist and/or cytotoxic agent can be administered alone, or in conjunction with either another agent as described above or with a pharmaceutically acceptable carrier, or both.
- the FGF antagonist/agonist and/or cytotoxic agent can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
- the FGF antagonist/agonist and/or cytotoxic agent can also be administered in a proform which is converted into its active metabolite, or more active metabolite in vivo.
- parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
- systemic administration means the administration of a FGF antagonist/agonist and/or cytotoxic agent, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
- the FGF antagonist/agonist and/or cytotoxic agent which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
- the present invention also concerns vaccines comprising an immunogenic amount of an FGF polypeptide, or a fragment thereof; an FGF receptor-derived polypeptide (FGFR polypeptide), or a fragment thereof, or a fragment of a proteoglycan (PG) that facilitates the binding of FGF to its receptors, dispersed in a physiologically acceptable, nontoxic vehicle, which amount is effective to immunize a subject, preferably a mammal, more preferably a human, against a neoplastic disease.
- FGFR polypeptide FGF receptor-derived polypeptide
- PG proteoglycan
- the FGF or FGFR polypeptides, or the PG may be synthesized or prepared recombinantly or otherwise biologically, to comprise one or more amino acid sequences co ⁇ esponding to one or more epitopes of the FGF or FGFR polypeptides, or the PG either in monomeric or multimeric form. Those polypeptides may then be inco ⁇ orated into vaccines capable of inducing protective immunity. Techniques for enhancing the antigenicity of such polypeptides include inco ⁇ oration into a multimeric structure, binding to a highly immunogenic protein carrier, for example, keyhole limpet hemocyanin (KLH), or diphtheria toxoid, and administration in combination with adjuvants or any other enhancers of immune response.
- KLH keyhole limpet hemocyanin
- an amino acid sequence co ⁇ esponding to an epitope of an FGF polypeptide either in monomeric or multimeric form may also be obtained by chemical synthetic means or by purification from biological sources including genetically modified microorganisms or their culture media. See Lerner, "Synthetic Vaccines", Sci. Am. 248(2): 66-74 (1983).
- the polypeptide may be combined in an amino acid sequence with other proteins/polypeptides including fragments of other proteins, as for example, when synthesized as a fusion protein, or linked to other antigenic or non-antigenic polypeptides of synthetic or biological origin.
- an epitope of an FGF or FGFR polypeptides, or the PG will be understood to include the practical possibility that, in some instances, amino acid sequence variations of a naturally occurring protein or polypeptide may be antigenic and confer protective immunity against neoplastic disease and/or anti-tumorigenic effects.
- Possible sequence variations include, without limitation, amino acid substitutions, extensions, deletions, truncations, inte ⁇ olations and combinations thereof.
- Such variations fall within the contemplated scope of the invention provided the polypeptide containing these variations is immunogenic and antibodies elicited by such a polypeptide cross-react with naturally occurring FGF polypeptides to a sufficient extent to provide protective immunity and/or anti-tumorigenic activity when administered as a vaccine.
- Such vaccine compositions can be combined with a physiologically acceptable medium, including immunologically acceptable diluents and carriers as well as commonly employed adjuvants such as Freund's Complete Adjuvant, saponin, alum, and the like.
- Administration would be in immunologically effective amounts of the FGF or FGFR polypeptides, or the PG, preferably in quantities providing unit doses of from 0.01 to 10.0 micrograms of immunologically active FGF or FGFR polypeptide, or the PG per kilogram of the recipient's body weight.
- Total protective doses may range from 0.1 to about 100 micrograms of antigen.
- anti-idiotype antibodies to FGF or FGFR polypeptide, or the PG are also useful as vaccines and can be similarly formulated.
- Mouse anti-human aFGF and bFGF monoclonal antibodies were obtained from Sigma; lactate dehydrogenase (LDH) assay, bromodeoxyuridine (BrdU) ELISA and human recombinant r-aFGF and r-bFGF from Boehringer Mannheim.
- LDH lactate dehydrogenase
- BrdU bromodeoxyuridine
- the anti-aFGF antibody reacts with naturally occurring aFGF and human recombinant aFGF and does not cross-react with bFGF (Ichimori, Y. et al (1991) Biochem. Biophys. Res. Commun. 17 '5:291-297).
- the anti-bFGF antibody was generated using the 18 kDa human r- bFGF, is specific for bFGF and does not cross-react with aFGF (Watanabe, H. et al. (1991) Biochem. Biophys. Res. Commun. 175:229-235).
- r-aFGF and r-bFGF are monomeric peptides and are identical to the 14 kDa human aFGF or the 18 kDa human bFGF, except for the extra methionine at the amino terminus (Jaye, M. et al. (1986) Science, 233:541-545; Bohlen, P. et al. (1985) EERS Letters 18:177-181).
- Human prostate PC3 tumor cells and rat normal intestinal epithelial I ⁇ C6 cells were obtained from the American Type Culture Collection.
- the rat MAT-LyLu tumor cells and PC3-LN cells were obtained from Dr. John Isaacs and Dr. Joy Ware, respectively.
- Paired primary and metastatic tumors were surgically removed from the same host. Fragments of the non-necrotic portions were cultured as histocultures. Single cell suspensions (>95% viability) were obtained by incubating tumor fragments ( ⁇ 1 g) with collagenase, EDTA, and trypsin. Histocultures (tumor fragments of ⁇ 1 mm 3 ) and monolayers were cultured in medium supplemented with 9% heat-inactivated fetal bovine serum (FBS) (Yen, W.C. et al. (1996; Pharm. Res. 13:1305-1312).
- FBS heat-inactivated fetal bovine serum
- CM Conditioned medium
- proteins were transfe ⁇ ed from polyacrylamide gel to a nitrocellulose filter by electrophoresis, followed by sequential incubation with 5% nonfat dry milk in 100 mM Tris/150 mM NaCl/0.1% Tween 20 (pH 7.6), and 5 microgram/ml aFGF or bFGF monoclonal antibody.
- the antibody-immunoreactive band was visualized using chemiluminescence blotting.
- the levels of aFGF and bFGF in the concentrated CM were quantified by comparing the intensity of their bands on Western blots to the intensity of the bands derived from standard curve samples of r-aFGF and r-bFGF.
- the standard curves were linear between 3 and 100 ng r-aFGF and between 1 and 160 ng r-bFGF.
- CM Pretreatment with CM and recombinant r-bFGF/r-aFGF
- CM Pretreatment with CM and recombinant r-bFGF/r-aFGF
- r-aFGF ad/or r-bFGF-containing medium, supplemented with 1% FBS (final protein concentration adjusted to 2 mg/ml).
- FBS final protein concentration adjusted to 2 mg/ml
- aFGF or bFGF was immunoprecipitated with their respective monoclonal antibody (1 microgram/ml), in the presence of Protein G PLUS/protein A agarose (Oncogene). This procedure reduced the bFGF level in the original CM to below the detection limit of 5 pg/ml by the ELISA (Oncogene), and the aFGF level in the concentrated CM to below the detection limit by Western blotting.
- This example describes three studies showing (a) a novel epigenetic mechanism of broad spectrum chemoresistance that is mediated by extracellular factors present in solid and metastatic tumors, and (b) loss of these factors upon removing tumors from metastatic sites and/or disrupting the tumor microenvironment.
- the results supporting these conclusions are provided in Table 1 below.
- the studies were performed using anticancer agents that have diverse structures and action mechanism, including paclitaxel (an antimicrotubule agent), doxorubicin (a topoisomerase II inhibitor) and 5- fluorouracil (an antimetabolite). Similar results were found for all three drugs.
- the first study compared the chemosensitivity in histocultures of rat primary and metastatic tumors, where the heterogeneous cell types and the 3-dimensional structure of solid tumors are maintained, to the chemosensitivity in the co ⁇ esponding monolayer cultures of cells obtained by trypsin-disaggregation of the same tumors.
- the 2- to 40-fold lower chemosensitivity in histocultures indicates that the unique environment in solid tumors played a role in chemoresistance.
- the second study shows that histocultures and early monolayer cultures of lung metastases were more resistant than lymph node metastases which in turn were more resistant than subcutaneous primary tumors, indicating that tumor location determined the extent of chemoresistance.
- Table 1 Loss of drug resistance, aFGF and bFGF upon disaggregation of metastatic tumors and upon passaging in monolayer cultures.
- Paired rat primary and metastatic tumors were cultured as histocultures or monolayers.
- tumors were treated with paclitaxel for 24 hours (12 pairs of primary and lymph node tumors and 2 pairs of primary and lung tumors), and with doxorubicin (3 pairs of primary and lymph node tumors) and 5-fluorouracil (2 pairs of primary and lung tumors) for 96 hours.
- monolayers cells were treated with drugs for 96 hours, and drug effect was measured as inhibition of bromodeoxyuridine inco ⁇ oration. NM, not measured.
- EXAMPLE II Induction of resistance to anticancer agents due to extracellular factors in solid and metastatic tumors
- This example describes the experiments confirming the induction of chemoresistance by extracellular factors in metastatic tumors, and indicating a progressive loss of these factors upon passaging metastatic tumor cells in monolayers.
- CM from rat tumor cultures was collected and evaluated for its effect on chemosensitivity. This and subsequent experiments were performed using rat primary tumor cells and human prostate tumor cells. Qualitatively similar results were obtained for both cell types, indicating the general nature of the observations ( Figure 1). CM derived from histocultures and early monolayer cultures of metastases (refe ⁇ ed to as active metastatic tumor CM) induced a 3- to 10-fold resistance to drugs (p ⁇ 0.05), whereas CM from late monolayer cultures of metastatic tumors and CM from primary tumors (refe ⁇ ed to as inactive CM) had no effect.
- EXAMPLE III Identification of bFGF and aFGF as some of the extracellular factors that induce resistance to anticancer agents
- CM conditioned media
- the active CM showed 2- to 7-fold higher concentrations of two proteins, which were identified by immunoblotting as aFGF (approximately 14 kDa) and bFGF (approximately 18 kDa).
- aFGF approximately 14 kDa
- bFGF approximately 18 kDa
- This example describes six studies which collectively show that (a) extracellular aFGF and bFGF are involved in the induction and maintenance of broad spectrum resistance to anticancer agents; and (b) bFGF but not aFGF was required to induce resistance whereas aFGF amplified the bFGF effect.
- the first study used specific inhibitors of extracellular aFGF and bFGF, i.e., monoclonal antibodies (Figure 2A).
- aFGF or bFGF did not alter drug activity, indicating no effect of the antibodies on the baseline chemosensitivity.
- the bFGF antibody produced a concentration-dependent reversal of the CM-induced chemoresistance, with complete reversal by 5 microgram/ml antibody, whereas a nonspecific antibody (i.e., non-immune rabbit IgG) had no effect.
- aFGF For aFGF, the antibody treatment partially reversed the CM-induced resistance; the maximum reversal was about 60% that was obtained with 1 microgram/ml antibody with no significant additional reversal at a 5 -fold higher concentration.
- the third study determined whether aFGF and/or bFGF are required for the resistance.
- Endogenous aFGF and/or bFGF were removed from the active CM by immunoprecipitation, and then reconstituted the CM using recombinant proteins.
- Combinations of r-aFGF/r-bFGF at concentrations as the endogenous proteins in the CM i.e., between 0.16 and 0.32 ng/ml r-aFGF plus 1 ng/ml r-bFGF
- CM i.e., between 0.16 and 0.32 ng/ml r-aFGF plus 1 ng/ml r-bFGF
- the chemoresistance observed above was measured primarily as antiproliferative drug effect.
- the sixth study measured the cell kill effect of drugs. Similar findings were observed, i.e., the active metastatic tumor CM and r-bFGF induced resistance to cell kill by drugs, whereas r-aFGF did not induce resistance but enhanced the effect of r-bFGF ( Figure 4). Therefore, the FGF-induced resistance applies to both antiproliferative and cell kill effects.
- EXAMPLE V In vitro data on the enhancement of sensitivity of tumor cells to anticancer agents using inhibitors of aFGF and bFGF
- This example shows that inhibitors of aFGF and/or bFGF enhanced the tumor sensitivity to anticancer agents.
- Figure 2A shows that inhibition of aFGF and/or bFGF using their respective monoclonal antibodies enhanced the cytotoxicity of paclitaxel, doxorubicin and 5- fluorouracil against human and rodent tumor cells.
- Figure 2B shows the same findings when anti-aFGF monoclonal antibody and/or anti-bFGF monoclonal antibody were used to remove aFGF and/or bFGF from the cell culture medium.
- Another inhibitor of aFGF and bFGF i.e., suramin, also reverses the FGF-induced resistance and enhances the activity of at least 58 anticancer agents under in vitro and/or in vivo conditions (see also Example VIII).
- Suramin is a negatively charged molecule that inhibits the action of multiple growth factors including aFGF and bFGF (Middaugh, C.R. et al. (1992) Biochem. 31 :9016-9024).
- Figure 5 shows the results of in vitro experiments demonstrating that addition of suramin produced a concentration-dependent reversal of the CM-induced resistance to paclitaxel, doxorubicin and 5-fluorouracil in rat MAT-LyLu tumor cells, human prostate PC3 tumor cells, and a metastatic subline of PC3, i.e., PC3-LN cells. Complete reversal was attained at between 10 to 15 ⁇ M suramin, which, as shown in Example VI, had no antitumor effect when used alone.
- FIG. 6 shows the concentration-response curves of suramin in the tumor cell lines used in the studies described in Examples V and VII.
- the concentration of suramin, when used alone, required to result in 50% reduction of bromodeoxyuridine inco ⁇ oration (i.e., IC50) were 235 micromolar in rat MAT-LyLu tumor cells, 93 micromolar in human prostate PC3 tumor cells, and 98 micromolar in human prostate PC3-LN tumor cells.
- IC 50 values are between 6- to 200-fold higher than its concentration needed to fully reverse the FGF-induced resistance (between 1 to 15 micromolar, see Examples V and VII and Table 2).
- suramin did not produce measurable cytotoxicity (i.e., ⁇ 10% reduction in cell number and/or proliferation index).
- the enhancement of the antitumor effect of anticancer drugs by suramin occurs at nontoxic concentrations of suramin.
- EXAMPLE VII Broad spectrum of anticancer agents exhibit aFGF/bFGF- induced resistance that is reversed by suramin
- EXAMPLE VIII aFGF bFGF-induced resistance to anticancer agents is detected in multiple cancer cell lines
- the drug effect was determined by the inhibition of BrdU incorporation.
- the drug effect was measured by the MTT assay, which measures the number of metabolically active cells (Alley, M.C. et al (1988) Cancer Res 48:589-601).
- r-aFGF amplified the r-bFGF effect by more than 50-fold (e.g. 1 ng/ml r-aFGF plus 1 ng/ml r-bFGF induced greater resistance than 50 ng/ml r-bFGF alone).
- CCRF-CEM human leukemic cell line
- r-aFGF 1 ng/ml
- r-bFGF 3 ng/ml
- FGF-induced resistance occurs in multiple human and rodent tumor cell lines.
- the BC 19 cell line is a subline of MCF7 transfected with m rl. * Indicates p ⁇ 0.05 compared to control.
- This example describes four studies that provide additional data on the enhancement of the antitumor effect of paclitaxel and doxorubicin by suramin in immunodeficient mice bearing several human xenograft tumors.
- mice Male Balb/c nu/nu mice, 6-8 weeks old. Animal care was in accordance with the guidelines at the Ohio State University.
- human tumor models were used, including (a) lung metastases derived from intravenous injection of human PC3-LN tumor cells, (b) lung tumors derived from direct injection of human PC3 cells in lungs, and (c) subcutaneously implanted PC3 tumors. Four studies were performed. In all studies, drug treatment was administered intravenously via a tail vein, after the tumor was established. The first and second studies used the intravenous PC3-LN lung metastasis model.
- human PC3-LN cells (10 6 cells in 0.1 ml physiologic saline) were injected intravenously, via a tail vein, into immunodeficient mice. This procedure results in metastasis to lungs in 100% of the animals (Ware, J.L. et al. (1985) Exp. Cell Biol. 53:163-169). After 4 weeks, tumor establishment was determined by visual examination of the lungs of two randomly selected animals, and drug treatment in the remaining animals was initiated when these two animals showed at least 5 tumor nodules of ⁇ 1 mm diameter.
- mice received intravenous injection (over 1 min) of 200 ⁇ l of either physiologic saline or a saline solution delivering a chemotherapeutic, 10 mg/kg suramin, or a combination of chemotherapeutic and suramin.
- the chemotherapeutic was doxorubicin (5 mg/kg) for the first study and paclitaxel (Taxol, 15 mg/kg) for the second study. Treatment was given twice weekly for three weeks. Preliminary pharmacokinetic data in rodents indicate that these doses would result in plasma concentrations of approximately 10 nM for doxorubicin, 5-7 nM for paclitaxel and 10 micromolar for suramin at 72 hours.
- the suramin concentration was sufficient to reverse the FGF- induced chemoresistance.
- the doxorubicin and paclitaxel concentrations are near or above their IC 5 oin the monolayer cultures of PC3-LN cells (i.e., 17 nM for doxorubicin and 8 nM for paclitaxel).
- the selected suramin dose has no in vivo antitumor activity against other mouse tumors (Chahinian, A.P. et al. (1998) J. Surg. Oncol. 67 : 104- 111 ; Shin, R., et al. (1997) Scand. J. Gastroenterol 32:824-828).
- mice were euthanized and their lungs removed, fixed in Bouin's solution to visualize tumor nodules, and then processed for histologic evaluation. Histologic sections (5 micron thickness) at a depth of between 200-300 ⁇ m from the ventral surface and containing all 5 lobes of the lungs were obtained. The lung surface area (counted as number of pixel) occupied by the tumor was calculated as a fraction of the total lung area, using Adobe PhotoShop. The number of tumor cells in residual tumors and the fraction of apoptotic cells in each tumor were also determined microscopically.
- apoptotic cells disappear over time, a second measure of the extent of apoptosis was the density of non-apoptotic cells in the residual tumors. This was determined by counting the number of non-apoptotic tumor cells in randomly selected microscopic fields at 400 x magnification. On average, ten fields per animal, or >1,500 cells in the control and suramin groups and >600 cells in the doxorubicin group were counted. In the case of combination therapy where fewer than 5 tumor nodules remained per animal, all residual cells (between 20 to 600 cells per animal) were counted.
- the average pretreatment weights for the four groups ranged from 21 g to 22 g. Animals that did not show visible tumors on the lung surface nor microscopic lesions in 5 random histologic sections are considered tumor-free. Mean ⁇ SD. *p ⁇ 0.05 compared to the control and suramin groups. t p ⁇ 0.05 compared to all other groups.
- I l l Table 5 Suramin enhances the in vivo antitumor effect of paclitaxel in mice bearing human lung metastases established by intravenous injection of tumor cells.
- the average pretreatment weights for the four groups ranged from 21 g to 22 g. Mean ⁇ SD. *p ⁇ 0.05 compared to the control and suramin groups. t p ⁇ 0.05 compared to all other groups.
- the third study shows enhancement of doxorubicin activity in lung tumors established by intra-organ tumor cell injection.
- PC3 cells were directly injected into the lungs of immunodeficient mice (2.5xl0 6 cells per lung). Tumor establishment (on day 5) was verified by visual examination of a randomly selected animal. The remaining animals were given intravenous bolus injection of doxorubicin (three doses of 10 mg/kg each given on day 5, 8 and 11) alone, suramin alone (three doses of 20 mg/kg), or a combination of both drugs. Animals were euthanized on day 12. Lungs were removed and examined visually for residual tumors. Histologic sections were obtained and examined microscopically, as described for the first two studies.
- the fourth study shows that suramin enhanced the antitumor effect of doxorubicin in subcutaneous bulky tumors.
- PC3 cells (5xl0 6 cells) were injected subcutaneously.
- Drug treatments suramin 10 mg/kg, doxorubicin 5 mg/kg, or a combination of both drugs, given twice weekly for 3 weeks.
- the average tumor size was 150 mg at the time of first treatment.
- Figure 7 A shows (a) a 3- to 4-fold increase of tumor size in the untreated control group and suramin group, indicating that suramin alone had no antitumor activity, (b) doxorubicin alone reduced the tumor growth but did not cause tumor regression, (c) doxorubicin + suramin combination reduced the tumor growth during the first week, followed by tumor regression until the end of the 3-week treatment.
- Results on the animal body weight ( Figure 7B) indicate (a) suramin alone did not cause body weight loss, (b) doxorubicin produced a 17% body weight loss, and (c) addition of suramin to doxorubicin did not enhance body weight loss.
- EXAMPLE X Relationship between aFGF and bFGF levels in tumor, tumor size, and tumor sensitivity to anticancer agents
- This example demonstrates a correlation between aFGF and bFGF level in tumor and tumor size, and a correlation between bFGF level in tumor and tumor sensitivity to anticancer agents.
- the first study examined the effect of the presence of tumor cells on the extracellular bFGF levels in tissues. Briefly, human prostate PC3 tumor cells were implanted intradermally or directly into the lungs of immunodeficient mice. Tumors were removed from animals and -10 mg were cultured as histocultures. The culture medium was collected at 24 hours and analyzed for bFGF.
- the bFGF level in PC3 cells was 2 pg/10 6 cells (approximately 2 pg/mg), 0.13 pg/mg in normal lung tissue, 0.62 pg/mg in normal skin tissue, 3.2 pg/mg in PC3-containing lung tumor, and 11.3 pg/mg in PC3-containing skin tumor.
- the bFGF levels in tumor-bearing tissues exceeded the sum of bFGF levels in tumor cells and normal tissues, indicating that the presence of tumor cells enhanced bFGF level.
- the enhancement was 25-fold in lungs and 18-fold in skin.
- the mouse brain contained 0.027 pg bFGF per mg tissue and the liver contained 0.636 pg bFGF per mg tissue. The results indicate (a) different bFGF levels in different tissues, and (b) presence of tumor cells significantly enhanced the bFGF levels.
- the second study examined the relationship between the extracellular bFGF level and tumor size.
- Human prostate PC3 tumor cells were implanted subcutaneously in immunodeficient mice. Subcutaneous tumor were removed from host animals after 1 to 7 weeks, and -200 mg were cultured as histocultures. The culture medium was collected at 24 hours and analyzed for bFGF concentration by ELISA.
- the bFGF level increased with time, from 27 pg/ml in week 1 tumor, to 56 pg/ml in week 2 tumor, to 77 pg/ml in week 3 tumor, and reached a plateau level of between 80 to 87 pg/ml between week 4 and week 7 tumors.
- the differences between the bFGF levels in weeks 1 , 2 and 3 are statistically significant. This indicates a positive correlation between bFGF level and tumor size.
- the third study examined the relationship between the levels of aFGF and bFGF in human tumors and tumor sensitivity to anticancer agents.
- This study was performed using 96 tumors obtained from human patients, including include bladder, breast, head and neck, ovarian and prostate tumors. Paclitaxel was used as the model drug. Briefly, histocultures of bladder tumors were treated with paclitaxel for 2 hours and the remaining tumors for 96 hours. The drug-induced antiproliferation was measured by inhibition of DNA precursor inco ⁇ oration, and apoptosis was measured by morphological changes and by labeling of nicked DNA.
- aFGF, bFGF and other proteins known to contribute to drug resistance i.e. the mdrl p-glycoprotein, p53 and bcl-2) were detected by immunohistochemical staining.
- bFGF expression was the best indicator of resistance to the antiproliferative effect and the overall cytotoxicity (i.e., antiproliferation plus apoptosis) of paclitaxel in tumors obtained from human patients (see Table 6 set forth below). Addition of aFGF to bFGF improves the correlation (Table 6).
- aFGF and bFGF in tumors are determined by the location of the tumor and the size of the tumor, and that the aFGF/bFGF level, in turn, determines the tumor sensitivity to anticancer agents.
- the varying FGF level in tumors indicates the use of FGF level for making therapeutic decision for individual patients.
- the best prognostic indicators are those that give the highest r 2 values as well as the lowest AIC values.
- Statistical analysis was performed using linear regression analysis using REG software. A p value of less than 0.05 is statistically significant.
- FGF-induced resistance to anticancer agents is a novel mechanism that is different from the previously reported mechanisms of chemoresistance that involve an enhancement of drug efflux and altered cell proliferation.
- Human prostate PC3 tumor cells and rat MAT-LyLu tumor cells were treated with 3 H-paclitaxel (1 nM for human PC3 cells and 10 nM for rat tumor cells), 14 C-doxorubicin (50 and 100 nM, respectively), and 3 H-5-fluorouracil (500 nM for both cells) (Au, J.L.-S. et al. (1998) supra), with or without with the active CM collected from histocultures of lung metastases or with r-bFGF.
- the extracellular drug concentrations were selected based on their IC 50 (50% inhibitory concentration) in human and rat cells.
- the plateau intracellular drug concentrations which were attained at 4 hours for all three drugs in PC3 cells, and 1 (doxorubicin and 5-fluorouracil) and 4 hours (paclitaxel) in rat cells, were measured.
- CM or r-bFGF Treatment with the CM or r-bFGF also did not alter the doubling time of exponentially growing cells, which remained unchanged at 17 and 24 hours for rat and PC3 tumor cells, respectively. Hence, the FGF-induced chemoresistance is not due to altered cell proliferation.
- the findings described herein demonstrate (a) a novel epigenetic mechanism by which cancer cells utilize the unique microenvironment of solid tumors and metastases to elude cytotoxic insult, (b) establish an important role of extracellular growth factors in tumor sensitivity to chemotherapy, and (c) indicate a new treatment paradigm using combinations of chemotherapy with aFGF/bFGF inhibitors.
- This example shows that treatment of non-cancerous intestinal epithelium with aFGF and bFGF protects these cells from the toxicity of anticancer agents, such as paclitaxel and doxorubicin.
- IEC6 normal rat intestinal epithelial cells
- IEC6 normal rat intestinal epithelial cells
- Cell culture assay experiments can be performed in the rat prostate MAT-LyLu tumor cells, and the human prostate PC3 tumor cells or its metastatic subline PC3-LN cells. If the requirements of the invention are met in any of the three cell cells, the choice and the dosage of the FGF antagonist is suitable for use in the invention. Preferably the PC3 cells are used.
- Human prostate PC3 tumor cells can be obtained from the American Type Culture Collection.
- the rat MAT-LyLu tumor cells and PC3-LN cells were obtained from Dr. John Isaacs (Johns Hopkins University) and Dr. Joy Ware (University of Virginia), respectively.
- the doubling time of PC3 and PC3-LN cells is approximately 24-hour, the doubling time ofMAT- MAT-LyLu cells is approximately 15-17 hr. All three cell lines should be cultured as monolayers in a humidified environment containing 5% CO2 and 95% air, at 37°C.
- PC 3 cells and PC3-LN cells should be maintained in RPMI 1640 medium supplemented with 9% heat-inactivated fetal bovine serum, 2 mM 1- glutamine, 100 ⁇ g/ml gentamicin, and 95 ⁇ g/ml cefotaxime.
- MAT-LyLu cells should be maintained in RPMI 1640 medium containing 100 ⁇ g/ml gentamicin, 95 ⁇ g/ml cefotaxime and 9% heat-inactivated fetal bovine serum.
- Cells are harvested from subconfluent cultures using trypsin and resuspended in fresh medium before plating.
- Cells with > 90% viability, as determined by trypan blue exclusion, are used to evaluate the cytotoxicity of an FGF antagonist, e.g., suramin.
- FGF antagonist e.g., suramin.
- Cells are plated in 96 well microtiter plates at a density such that confluence would not be achieved at the end of the drug treatment period. Cells are allowed to attach to the plate surface by growing in drug-free medium for 20 to 24 hr. Afterward, cells are incubated with the FGF antagonist (one example used 0.2 ml of suramin)-containing culture medium, at concentrations spanning at least 4 log scales.
- the drug effect should be measured as inhibition of BrdU inco ⁇ oration, e.g., according to the Cell Proliferation ELISA BrdU (Boehringer Mannheim).
- EXAMPLE XVI Inhibition of FGF binding to FGF receptors This example describes the inhibition of the binding of FGF to FGF receptors by FGF antagonists.
- FGF antagonists i.e., suramin, heparin, low molecular weight heparin, heparan sulfate
- FGF receptors FGF receptors in human prostate cancer PC3 cells and human breast cancer MCF7 cells
- FGF antagonists i.e., suramin, heparin, low molecular weight heparin, heparan sulfate
- FGF receptors in human prostate cancer PC3 cells and human breast cancer MCF7 cells were studied. Briefly, cells were plated at 1 X 10 5 cells per 16 mm well on 24-well plates and were allowed to settle for 48 hours before binding experiment. On the day of the experiment, cells were incubated for 2 hours at 37°C in serum-free DMEM supplemented with 0.15%) gelatin. Cells were then washed twice with ice-cold phosphate buffered saline.
- Differential display was used to identify the down-stream genes that are involved in the bFGF-induced multidrug resistance. These genes were identified by comparing the effect of bFGF on the expression of these genes in a cell line that demonstrates bFGF-induced chemoresistance (i.e. human prostate cancer PC3 cells) with that in a cell line which does not show bFGF-induced chemoresistance (i.e. human head and neck cancer FaDu cells). By this method, the genes that were altered by bFGF treatment in PC3 cells but not in FaDu cells were identified. The identified genes are likely to be associated with the bFGF-induced multidrug resistance.
- bFGF-induced chemoresistance i.e. human prostate cancer PC3 cells
- FaDu cells i.e. human head and neck cancer FaDu cells
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU57903/00A AU780454B2 (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
EP00943429A EP1206234A4 (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
CA002377385A CA2377385A1 (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
IL14687200A IL146872A0 (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
JP2001501171A JP2003503313A (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
IL146872A IL146872A (en) | 1999-06-03 | 2001-12-02 | Use of cytotoxic agent and suramin for the manufacture of pharmaceutical compositions |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13734599P | 1999-06-03 | 1999-06-03 | |
US60/137,345 | 1999-06-03 | ||
US16598399P | 1999-11-17 | 1999-11-17 | |
US60/165,983 | 1999-11-17 | ||
US17203199P | 1999-12-23 | 1999-12-23 | |
US60/172,031 | 1999-12-23 | ||
US18744500P | 2000-03-07 | 2000-03-07 | |
US60/187,445 | 2000-03-07 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2000074634A2 true WO2000074634A2 (en) | 2000-12-14 |
WO2000074634A3 WO2000074634A3 (en) | 2001-08-23 |
WO2000074634A9 WO2000074634A9 (en) | 2002-09-26 |
Family
ID=27495263
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/040103 WO2000074634A2 (en) | 1999-06-03 | 2000-06-05 | Methods and compositions for modulating cell proliferation and cell death |
Country Status (8)
Country | Link |
---|---|
US (2) | US6599912B1 (en) |
EP (1) | EP1206234A4 (en) |
JP (1) | JP2003503313A (en) |
KR (1) | KR100903243B1 (en) |
AU (1) | AU780454B2 (en) |
CA (1) | CA2377385A1 (en) |
IL (2) | IL146872A0 (en) |
WO (1) | WO2000074634A2 (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1328264A1 (en) * | 2000-07-25 | 2003-07-23 | PHARMACIA & UPJOHN COMPANY | Use of estramustine phosphate in the treatment of bone metastasis |
JP2005508920A (en) * | 2001-10-03 | 2005-04-07 | セレーター テクノロジーズ インコーポレイテッド | Composition for delivering a concomitant drug |
US7071164B2 (en) | 2001-08-16 | 2006-07-04 | Kimberly-Clark Worldwide, Inc. | Anti-cancer and wound healing compounds |
US7094754B2 (en) | 2001-08-16 | 2006-08-22 | Kimberly-Clark Worldwide, Inc. | Anti-aging and wound healing compounds |
US7148194B2 (en) | 2002-12-30 | 2006-12-12 | Kimberly-Clark Worldwide, Inc. | Method to increase fibronectin |
WO2006009805A3 (en) * | 2004-06-18 | 2007-01-04 | Genentech Inc | Combination of a chemotherapeutic agent and an antagonist of a gene product for treating tumors |
EP1742961A2 (en) * | 2004-02-13 | 2007-01-17 | Boston Biomedical Research Institute | Inhibition of fgf signaling |
JP2007504194A (en) * | 2003-09-05 | 2007-03-01 | ゲンチウム エスピーエー | Anti-tumor preparation containing defibrotide alone or in combination with other anti-tumor agents |
US7186693B2 (en) | 2001-08-16 | 2007-03-06 | Kimberly - Clark Worldwide, Inc. | Metalloproteinase inhibitors for wound healing |
US7189700B2 (en) | 2003-06-20 | 2007-03-13 | Kimberly-Clark Worldwide, Inc. | Anti-chrondrosarcoma compounds |
US7196162B2 (en) | 2001-08-16 | 2007-03-27 | Kimberly-Clark Worldwide, Inc. | Anti-aging and wound healing compounds |
US7250416B2 (en) | 2005-03-11 | 2007-07-31 | Supergen, Inc. | Azacytosine analogs and derivatives |
US7276228B2 (en) | 2001-04-24 | 2007-10-02 | Supergen, Inc. | Methods for treating hematological disorders through inhibition of DNA methylation and histone deacetylase |
US7700567B2 (en) | 2005-09-29 | 2010-04-20 | Supergen, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
WO2010140795A2 (en) * | 2009-06-01 | 2010-12-09 | (주)차바이오앤디오스텍 | Human-placenta-like composition containing a human-placenta-derived growth factor and cytokines, and cosmetic use thereof |
US7850990B2 (en) | 2001-10-03 | 2010-12-14 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
US8980862B2 (en) | 2010-11-12 | 2015-03-17 | Gentium S.P.A. | Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD) |
US9381207B2 (en) | 2011-08-30 | 2016-07-05 | Astex Pharmaceuticals, Inc. | Drug formulations |
US9902952B2 (en) | 2012-06-22 | 2018-02-27 | Gentrum S.R.L. | Euglobulin-based method for determining the biological activity of defibrotide |
US10058507B2 (en) | 2001-10-03 | 2018-08-28 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
US10393731B2 (en) | 2014-11-27 | 2019-08-27 | Gentium S.R.L. | Cellular-based method for determining the biological activity of defibrotide |
US10485764B2 (en) | 2015-07-02 | 2019-11-26 | Otsuka Pharmaceutical Co., Ltd. | Lyophilized pharmaceutical compositions |
US10519190B2 (en) | 2017-08-03 | 2019-12-31 | Otsuka Pharmaceutical Co., Ltd. | Drug compound and purification methods thereof |
RU2723091C2 (en) * | 2015-03-23 | 2020-06-08 | Дойчес Кребсфоршунгсцентрум Штифтунг Дес Эффентлихен Рехтс | Oligonucleotide sequences aimed at the transcription factor tsc22d4, for treating insulin resistance |
Families Citing this family (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030180290A1 (en) * | 1995-06-07 | 2003-09-25 | Idec Pharmaceuticals Corporation | Anti-CD80 antibody having ADCC activity for ADCC mediated killing of B cell lymphoma cells alone or in combination with other therapies |
JP2003531149A (en) * | 2000-04-13 | 2003-10-21 | ザ・ロツクフエラー・ユニバーシテイ | Enhancement of antibody-derived immune response |
CA2436180C (en) * | 2001-01-31 | 2011-11-08 | Idec Pharmaceutical Corporation | Immunoregulatory antibodies and uses thereof |
US20030103971A1 (en) * | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
US20030059375A1 (en) * | 2001-08-20 | 2003-03-27 | Transave, Inc. | Method for treating lung cancers |
CA2457148A1 (en) * | 2001-08-20 | 2003-02-27 | Transave, Inc. | Treatment of cancers by inhalation of stable platinum-containing formulations |
WO2003026574A2 (en) * | 2001-09-24 | 2003-04-03 | Au Jessie L-S | Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy |
JP4694128B2 (en) * | 2002-01-30 | 2011-06-08 | ザ ブライハム アンド ウイメンズ ホスピタル, インコーポレイテッド | Compositions and methods related to TIM-3, Th1-specific cell surface molecules |
EP1490027A4 (en) * | 2002-03-05 | 2010-11-10 | Transave Inc | Methods for entrapment of bioactive agent in a liposome or lipid complex |
US9186322B2 (en) * | 2002-08-02 | 2015-11-17 | Insmed Incorporated | Platinum aggregates and process for producing the same |
US20040101553A1 (en) * | 2002-08-02 | 2004-05-27 | Transave, Inc. | Platinum aggregates and process for producing the same |
US7718189B2 (en) * | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
US7879351B2 (en) * | 2002-10-29 | 2011-02-01 | Transave, Inc. | High delivery rates for lipid based drug formulations, and methods of treatment thereof |
CN1747738B (en) * | 2002-10-29 | 2010-11-24 | 川塞夫有限公司 | Sustained release of antifectives |
KR20050114241A (en) * | 2003-03-19 | 2005-12-05 | 가부시키가이샤 디나벡크 겐큐쇼 | Method of treating inflammtory disease associated with bone destruction |
KR20050116166A (en) * | 2003-04-28 | 2005-12-09 | 파마시아 앤드 업존 캄파니 엘엘씨 | Use of irinotecan for treatment of resistant breast cancer |
US20050282893A1 (en) * | 2004-01-30 | 2005-12-22 | Au Jessie L | Methods and compositions for using suramin, pentosan, polysulfate, telomerase antisense and telomerase inhibitors |
US20050249822A1 (en) * | 2004-03-18 | 2005-11-10 | Transave, Inc. | Administration of cisplatin by inhalation |
WO2005112957A1 (en) * | 2004-05-21 | 2005-12-01 | Transave, Inc. | Treatment of lung diseases and pre-lung disease conditions |
EP2290071B1 (en) * | 2004-05-28 | 2014-12-31 | Asuragen, Inc. | Methods and compositions involving microRNA |
RO121676B1 (en) * | 2004-08-18 | 2008-02-28 | Institutul Oncologic "Prof.Dr. Al. Trestioreanu" | Method for improving cytostatic tolerance of the body |
US20060246124A1 (en) * | 2004-11-08 | 2006-11-02 | Pilkiewicz Frank G | Methods of treating cancer with lipid-based platinum compound formulations administered intraperitoneally |
EP2281887A1 (en) | 2004-11-12 | 2011-02-09 | Asuragen, Inc. | Methods and compositions involving miRNA and miRNA inhibitor molecules |
US20060183712A1 (en) * | 2005-02-17 | 2006-08-17 | The Texas A&M University System | Affinity purified heparin/heparan sulfate for controlling the biological activity of the FGF receptor |
US8999706B2 (en) * | 2005-04-12 | 2015-04-07 | The Trustees Of The University Of Pennsylvania | Methods for preparation of human hair-follicle derived multipotent adult stem cells |
US20060283742A1 (en) * | 2005-06-16 | 2006-12-21 | Canel Lightning Co. Ltd. | Multi-lamp display packaging for lamps with collapsible lampshades |
CA2619568A1 (en) * | 2005-08-19 | 2007-03-01 | Government Of The United States Of America, Represented By The Secretary , Department Of Health And Human Services | Topical formulations of histone deacetylase inhibitors and methods of using the same |
US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
US20070190181A1 (en) * | 2005-11-08 | 2007-08-16 | Pilkiewicz Frank G | Methods of treating cancer with lipid-based platinum compound forumulations administered intravenously |
US20070190180A1 (en) * | 2005-11-08 | 2007-08-16 | Pilkiewicz Frank G | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intravenously |
US20070190182A1 (en) * | 2005-11-08 | 2007-08-16 | Pilkiewicz Frank G | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
WO2007064658A2 (en) * | 2005-11-30 | 2007-06-07 | Transave, Inc. | Safe and effective methods of administering therapeutic agents |
WO2007065016A2 (en) * | 2005-12-02 | 2007-06-07 | Au Jessie L S | Methods and compositions to improve activity and reduce toxicity of stents |
DK1962805T3 (en) | 2005-12-08 | 2016-09-26 | Insmed Inc | Lipid-based compositions of the anti-infective agents for the treatment of lung infections |
US20070197599A1 (en) * | 2006-02-02 | 2007-08-23 | Matier William L | Hydroxylamines and derivatives as anti-angiogenic agents |
JP2010510964A (en) * | 2006-09-19 | 2010-04-08 | アシュラジェン インコーポレイテッド | MiR-15, miR-26, miR-31, miR-145, miR-147, miR-188, miR-215, miR-216, miR-331, mmu-miR-292 as targets for therapeutic intervention Genes and pathways regulated by 3p |
AU2007299828C1 (en) * | 2006-09-19 | 2014-07-17 | Interpace Diagnostics, Llc | MicroRNAs differentially expressed in pancreatic diseases and uses thereof |
US20080085881A1 (en) * | 2006-10-06 | 2008-04-10 | Aimery De Gramont | Stop-and-go oxaliplatin treatment regimens |
EP1918376A1 (en) * | 2006-11-03 | 2008-05-07 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | FGFR4 promotes cancer cell resistance in response to chemotherapeutic drugs |
AU2007333109A1 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Functions and targets of let-7 micro RNAs |
CA2671294A1 (en) * | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Mir-21 regulated genes and pathways as targets for therapeutic intervention |
CN101622349A (en) * | 2006-12-08 | 2010-01-06 | 奥斯瑞根公司 | miR-20 regulated genes and pathways as targets for therapeutic intervention |
US20090175827A1 (en) * | 2006-12-29 | 2009-07-09 | Byrom Mike W | miR-16 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
WO2008137717A1 (en) * | 2007-05-04 | 2008-11-13 | Transave, Inc. | Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods and uses thereof |
US9333214B2 (en) | 2007-05-07 | 2016-05-10 | Insmed Incorporated | Method for treating pulmonary disorders with liposomal amikacin formulations |
US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US20090131354A1 (en) * | 2007-05-22 | 2009-05-21 | Bader Andreas G | miR-126 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
US20090232893A1 (en) * | 2007-05-22 | 2009-09-17 | Bader Andreas G | miR-143 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
WO2008154333A2 (en) * | 2007-06-08 | 2008-12-18 | Asuragen, Inc. | Mir-34 regulated genes and pathways as targets for therapeutic intervention |
WO2008156644A2 (en) * | 2007-06-14 | 2008-12-24 | Frank David A | Stat modulators |
US8361714B2 (en) | 2007-09-14 | 2013-01-29 | Asuragen, Inc. | Micrornas differentially expressed in cervical cancer and uses thereof |
WO2009052386A1 (en) * | 2007-10-18 | 2009-04-23 | Asuragen, Inc. | Micrornas differentially expressed in lung diseases and uses thereof |
WO2009070805A2 (en) * | 2007-12-01 | 2009-06-04 | Asuragen, Inc. | Mir-124 regulated genes and pathways as targets for therapeutic intervention |
WO2009086156A2 (en) * | 2007-12-21 | 2009-07-09 | Asuragen, Inc. | Mir-10 regulated genes and pathways as targets for therapeutic intervention |
EP2260110B1 (en) * | 2008-02-08 | 2014-11-12 | Asuragen, INC. | miRNAs DIFFERENTIALLY EXPRESSED IN LYMPH NODES FROM CANCER PATIENTS |
WO2009111643A2 (en) * | 2008-03-06 | 2009-09-11 | Asuragen, Inc. | Microrna markers for recurrence of colorectal cancer |
WO2009154835A2 (en) * | 2008-03-26 | 2009-12-23 | Asuragen, Inc. | Compositions and methods related to mir-16 and therapy of prostate cancer |
WO2009126172A1 (en) * | 2008-04-11 | 2009-10-15 | The Trustees Of Columbia University In The City Of New York | Resistance to polyphenon e due to increased bcl-2 expression |
US8258111B2 (en) | 2008-05-08 | 2012-09-04 | The Johns Hopkins University | Compositions and methods related to miRNA modulation of neovascularization or angiogenesis |
WO2009155504A2 (en) * | 2008-06-20 | 2009-12-23 | The Children's Medical Center Corporation | Methods for the modulation of angiogenesis |
WO2010056737A2 (en) * | 2008-11-11 | 2010-05-20 | Mirna Therapeutics, Inc. | Methods and compositions involving mirnas in cancer stem cells |
US8491927B2 (en) | 2009-12-02 | 2013-07-23 | Nimble Epitech, Llc | Pharmaceutical composition containing a hypomethylating agent and a histone deacetylase inhibitor |
US8445517B2 (en) | 2009-12-11 | 2013-05-21 | Dana-Farber Cancer Institute | Stat modulators |
WO2012116328A2 (en) | 2011-02-24 | 2012-08-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Bad phosphorylation determines ovarian cancer chemo-sensitivity and patient survival |
US9644241B2 (en) | 2011-09-13 | 2017-05-09 | Interpace Diagnostics, Llc | Methods and compositions involving miR-135B for distinguishing pancreatic cancer from benign pancreatic disease |
EP2776043B1 (en) * | 2011-11-11 | 2018-02-21 | Millennium Pharmaceuticals, Inc. | Biomarkers of response to proteasome inhibitors |
LT2852391T (en) | 2012-05-21 | 2022-03-10 | Insmed Incorporated | Systems for treating pulmonary infections |
MX356830B (en) | 2012-07-13 | 2018-06-15 | Shin Nippon Biomedical Laboratories Ltd | Chiral nucleic acid adjuvant. |
US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
AU2013352259B2 (en) | 2012-11-29 | 2018-06-14 | Insmed Incorporated | Stabilized vancomycin formulations |
WO2014124412A2 (en) * | 2013-02-11 | 2014-08-14 | President And Fellows Of Harvard College | Methods and compounds for the inhibition of cellular proliferation |
ES2926985T3 (en) | 2014-05-15 | 2022-10-31 | Insmed Inc | Methods for treating nontuberculous mycobacterial lung infections |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
EP3773505A4 (en) | 2018-03-30 | 2021-12-22 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5574026A (en) * | 1994-12-13 | 1996-11-12 | American Cyanamid Company | Methods for inhibiting angiogenesis proliferation of endothelial or tumor cells and tumor growth |
US5716981A (en) * | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252718A (en) * | 1986-04-22 | 1993-10-12 | The Salk Institute For Biological Studies | Fibroblast growth factor antagonists |
US5102870A (en) | 1989-04-14 | 1992-04-07 | Schering Ag | Treatment and prevention of oral mucositis with growth factors |
JPH04224522A (en) | 1990-04-27 | 1992-08-13 | Merck & Co Inc | Therapeutic or prophylactic method for alopecia using composition containing fibroblast growth factor |
US5486509A (en) | 1991-06-28 | 1996-01-23 | University Of Miami | Method of preventing and treating chemotherapy-induced alopecia |
US5587368A (en) * | 1993-11-30 | 1996-12-24 | New York University | Administration of a 27-hydroxycholesterol or related compound or sterol-27-hydroxylase stimulant to prevent restenosis following vascular endothelial injury |
US5783568A (en) | 1994-06-10 | 1998-07-21 | Sugen, Inc. | Methods for treating cancer and other cell proliferative diseases |
US5597830A (en) | 1994-12-20 | 1997-01-28 | Warner-Lambert Company | Combination chemotherapy |
US5773252A (en) | 1995-06-05 | 1998-06-30 | Human Genome Sciences, Inc. | Fibroblast growth factor 15 |
JPH1149701A (en) * | 1997-08-04 | 1999-02-23 | Toagosei Co Ltd | Anticancer agent |
GB9727524D0 (en) | 1997-12-31 | 1998-02-25 | Pharmacia & Upjohn Spa | Synergistic antitumor composition containing a biologically active ureido compound |
PL348634A1 (en) | 1998-05-15 | 2002-06-03 | Imclone Systems Inc | Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases |
US6420335B1 (en) | 1998-06-15 | 2002-07-16 | Dana Farber Cancer Institute, Inc. | Combination of radiotherapy and anti-angiogenic factors |
-
2000
- 2000-06-05 JP JP2001501171A patent/JP2003503313A/en active Pending
- 2000-06-05 EP EP00943429A patent/EP1206234A4/en not_active Withdrawn
- 2000-06-05 AU AU57903/00A patent/AU780454B2/en not_active Ceased
- 2000-06-05 WO PCT/US2000/040103 patent/WO2000074634A2/en active IP Right Grant
- 2000-06-05 CA CA002377385A patent/CA2377385A1/en not_active Abandoned
- 2000-06-05 US US09/587,559 patent/US6599912B1/en not_active Expired - Lifetime
- 2000-06-05 IL IL14687200A patent/IL146872A0/en active IP Right Grant
- 2000-06-05 KR KR1020017015591A patent/KR100903243B1/en not_active IP Right Cessation
-
2001
- 2001-12-02 IL IL146872A patent/IL146872A/en not_active IP Right Cessation
-
2003
- 2003-06-18 US US10/464,018 patent/US7625860B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5716981A (en) * | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
US5574026A (en) * | 1994-12-13 | 1996-11-12 | American Cyanamid Company | Methods for inhibiting angiogenesis proliferation of endothelial or tumor cells and tumor growth |
Non-Patent Citations (2)
Title |
---|
See also references of EP1206234A2 * |
Stratagene catalog, "Gene Characterization Kits", 1988, page 39, XP002938362 * |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1328264A4 (en) * | 2000-07-25 | 2004-01-28 | Upjohn Co | Use of estramustine phosphate in the treatment of bone metastasis |
EP1328264A1 (en) * | 2000-07-25 | 2003-07-23 | PHARMACIA & UPJOHN COMPANY | Use of estramustine phosphate in the treatment of bone metastasis |
US7276228B2 (en) | 2001-04-24 | 2007-10-02 | Supergen, Inc. | Methods for treating hematological disorders through inhibition of DNA methylation and histone deacetylase |
US7186693B2 (en) | 2001-08-16 | 2007-03-06 | Kimberly - Clark Worldwide, Inc. | Metalloproteinase inhibitors for wound healing |
US7071164B2 (en) | 2001-08-16 | 2006-07-04 | Kimberly-Clark Worldwide, Inc. | Anti-cancer and wound healing compounds |
US7094754B2 (en) | 2001-08-16 | 2006-08-22 | Kimberly-Clark Worldwide, Inc. | Anti-aging and wound healing compounds |
US7196162B2 (en) | 2001-08-16 | 2007-03-27 | Kimberly-Clark Worldwide, Inc. | Anti-aging and wound healing compounds |
US9271931B2 (en) | 2001-10-03 | 2016-03-01 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
US10058507B2 (en) | 2001-10-03 | 2018-08-28 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
US10722464B2 (en) | 2001-10-03 | 2020-07-28 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
US7850990B2 (en) | 2001-10-03 | 2010-12-14 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
JP2005508920A (en) * | 2001-10-03 | 2005-04-07 | セレーター テクノロジーズ インコーポレイテッド | Composition for delivering a concomitant drug |
JP2010180210A (en) * | 2001-10-03 | 2010-08-19 | Celator Pharmaceuticals Inc | Composition for delivery of drug combination |
US7148194B2 (en) | 2002-12-30 | 2006-12-12 | Kimberly-Clark Worldwide, Inc. | Method to increase fibronectin |
US7189700B2 (en) | 2003-06-20 | 2007-03-13 | Kimberly-Clark Worldwide, Inc. | Anti-chrondrosarcoma compounds |
US7795225B2 (en) | 2003-06-20 | 2010-09-14 | Kimberly-Clark Worldwide, Inc. | Anti-chrondrosarcoma compounds |
JP2007504194A (en) * | 2003-09-05 | 2007-03-01 | ゲンチウム エスピーエー | Anti-tumor preparation containing defibrotide alone or in combination with other anti-tumor agents |
US8551967B2 (en) | 2003-09-05 | 2013-10-08 | Gentium Spa | Formulations with anti-tumour action |
US7968527B2 (en) | 2004-02-13 | 2011-06-28 | Boston Biomedical Research Institute | Inhibition of FGF signaling |
EP1742961A4 (en) * | 2004-02-13 | 2009-07-15 | Boston Biomedical Res Inst | Inhibition of fgf signaling |
EP1742961A2 (en) * | 2004-02-13 | 2007-01-17 | Boston Biomedical Research Institute | Inhibition of fgf signaling |
AU2005265067B2 (en) * | 2004-06-18 | 2010-12-16 | Genentech, Inc. | Combination of a chemotherapeutic agent and an antagonist of a gene product for treating tumors |
WO2006009805A3 (en) * | 2004-06-18 | 2007-01-04 | Genentech Inc | Combination of a chemotherapeutic agent and an antagonist of a gene product for treating tumors |
US8147827B2 (en) | 2004-06-18 | 2012-04-03 | Genentech, Inc. | Tumor treatment |
US7250416B2 (en) | 2005-03-11 | 2007-07-31 | Supergen, Inc. | Azacytosine analogs and derivatives |
US8461123B2 (en) | 2005-09-29 | 2013-06-11 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
US10456415B2 (en) | 2005-09-29 | 2019-10-29 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
US9358248B2 (en) | 2005-09-29 | 2016-06-07 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
US10933079B2 (en) | 2005-09-29 | 2021-03-02 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
US9480698B2 (en) | 2005-09-29 | 2016-11-01 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
US7700567B2 (en) | 2005-09-29 | 2010-04-20 | Supergen, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
WO2010140795A2 (en) * | 2009-06-01 | 2010-12-09 | (주)차바이오앤디오스텍 | Human-placenta-like composition containing a human-placenta-derived growth factor and cytokines, and cosmetic use thereof |
WO2010140795A3 (en) * | 2009-06-01 | 2011-04-21 | (주)차바이오앤디오스텍 | Human-placenta-like composition containing a human-placenta-derived growth factor and cytokines, and cosmetic use thereof |
US8980862B2 (en) | 2010-11-12 | 2015-03-17 | Gentium S.P.A. | Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD) |
US9539277B2 (en) | 2010-11-12 | 2017-01-10 | Gentium S.R.L. | Defibrotide for use in prophylaxis and/or treatment of graft versus host disease (GVHD) |
US9867843B2 (en) | 2010-11-12 | 2018-01-16 | Gentium S.R.L. | Defibrotide for use in prophylaxis and/or treatment of graft versus host disease (GVHD) |
US10517886B2 (en) | 2011-08-30 | 2019-12-31 | Astex Pharmaceuticals, Inc. | Drug formulations |
US9913856B2 (en) | 2011-08-30 | 2018-03-13 | Astex Pharmaceuticals, Inc. | Drug formulations |
US9381207B2 (en) | 2011-08-30 | 2016-07-05 | Astex Pharmaceuticals, Inc. | Drug formulations |
US9902952B2 (en) | 2012-06-22 | 2018-02-27 | Gentrum S.R.L. | Euglobulin-based method for determining the biological activity of defibrotide |
US11085043B2 (en) | 2012-06-22 | 2021-08-10 | Gentium S.R.L. | Euglobulin-based method for determining the biological activity of defibrotide |
US11236328B2 (en) | 2012-06-22 | 2022-02-01 | Gentium S.R.L. | Euglobulin-based method for determining the biological activity of defibrotide |
US11746348B2 (en) | 2012-06-22 | 2023-09-05 | Gentium S.R.L. | Euglobulin-based method for determining the biological activity of defibrotide |
US10393731B2 (en) | 2014-11-27 | 2019-08-27 | Gentium S.R.L. | Cellular-based method for determining the biological activity of defibrotide |
RU2723091C2 (en) * | 2015-03-23 | 2020-06-08 | Дойчес Кребсфоршунгсцентрум Штифтунг Дес Эффентлихен Рехтс | Oligonucleotide sequences aimed at the transcription factor tsc22d4, for treating insulin resistance |
US10485764B2 (en) | 2015-07-02 | 2019-11-26 | Otsuka Pharmaceutical Co., Ltd. | Lyophilized pharmaceutical compositions |
US10519190B2 (en) | 2017-08-03 | 2019-12-31 | Otsuka Pharmaceutical Co., Ltd. | Drug compound and purification methods thereof |
Also Published As
Publication number | Publication date |
---|---|
US20040010001A1 (en) | 2004-01-15 |
JP2003503313A (en) | 2003-01-28 |
IL146872A (en) | 2006-10-31 |
AU780454B2 (en) | 2005-03-24 |
US6599912B1 (en) | 2003-07-29 |
US7625860B2 (en) | 2009-12-01 |
EP1206234A4 (en) | 2005-06-01 |
WO2000074634A9 (en) | 2002-09-26 |
CA2377385A1 (en) | 2000-12-14 |
KR100903243B1 (en) | 2009-06-17 |
IL146872A0 (en) | 2002-08-14 |
WO2000074634A3 (en) | 2001-08-23 |
EP1206234A2 (en) | 2002-05-22 |
KR20020019924A (en) | 2002-03-13 |
AU5790300A (en) | 2000-12-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7625860B2 (en) | Methods and compositions for modulating cell proliferation and cell death | |
ES2929614T3 (en) | Anti-MUC16 antibodies and uses thereof | |
JP7001731B2 (en) | Use of bacteria, bacterial products, and other immunomodulatory entities in combination with anti-CTLA-4 and / or anti-PD-1 antibodies to treat solid tumor malignancies | |
JP6385277B2 (en) | Anti-CEACAM1 recombinant antibody for cancer treatment | |
DE60317677T2 (en) | OX40 (= CD134) RECEPTOR AGONISTS AND THERAPEUTIC USES | |
JP4857259B2 (en) | Use of anti-α5β1 antibodies to inhibit cancer cell growth | |
CN107135654A (en) | Giant cell drinks the anti-CD46 antibody of the mankind and target on cancer therapy | |
US20030082188A1 (en) | Treatment of prostate cancer by inhibitors of NCAM2 | |
JP2002539076A (en) | Methods and compositions for inhibiting angiogenesis | |
CN104768579A (en) | Methods of treating neuroendocrine tumors using Wnt pathway-binding agents | |
US20220289831A1 (en) | Use of beta-catenin as a biomarker for treating cancers using anti-dkk-1 antibody | |
WO2005019270A2 (en) | Endotheliase-2 ligands | |
JP2003527441A (en) | Drugs that block cell cycle and drugs that contain antibodies | |
JP6941565B2 (en) | Compounds and compositions useful for treating or preventing cancer metastasis, and their usage | |
EP2984108B1 (en) | Anti-s100a7 antibodies for the treatment and diagnosis of cancer | |
CN112739716A (en) | Methods of treating cancer using anti-PD-1 antibodies in combination with anti-tissue factor antibody-drug conjugates | |
KR20220131223A (en) | How to use a DKK-1 inhibitor to treat cancer | |
US20050281821A1 (en) | Method and composition for angiogenesis inhibition | |
KR20120123619A (en) | Polypeptide compounds for inhibiting angiogenesis and tumor growth | |
RU2361614C2 (en) | APPLICATION OF ANTIBODIES AGAINST α5β1 FOR INHIBITION OF CANCER CELLS PROLIFERATION |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US US US US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2377385 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 501171 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020017015591 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 57903/00 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000943429 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020017015591 Country of ref document: KR |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2000943429 Country of ref document: EP |
|
AK | Designated states |
Kind code of ref document: C2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US US US US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: C2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
COP | Corrected version of pamphlet |
Free format text: PAGES 1-124, DESCRIPTION, REPLACED BY NEW PAGES 1-124; PAGES 125-135, CLAIMS, REPLACED BY NEW PAGES125-135; PAGES 1/7-7/7, DRAWINGS, ADDED |
|
WWG | Wipo information: grant in national office |
Ref document number: 57903/00 Country of ref document: AU |