Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS20030216359 A1
Publication typeApplication
Application numberUS 10/429,840
Publication dateNov 20, 2003
Filing dateMay 5, 2003
Priority dateAug 29, 1997
Also published asDE69824622D1, DE69824622T2, EP1030670A1, EP1030670B1, EP1491198A1, US6087350, US6559139, US20030176403, US20080003304, WO1999016451A1
Publication number10429840, 429840, US 2003/0216359 A1, US 2003/216359 A1, US 20030216359 A1, US 20030216359A1, US 2003216359 A1, US 2003216359A1, US-A1-20030216359, US-A1-2003216359, US2003/0216359A1, US2003/216359A1, US20030216359 A1, US20030216359A1, US2003216359 A1, US2003216359A1
InventorsCandace Johnson, Donald Trump
Original AssigneeUniversity Of Pittsburgh Of The Commonwealth System Of Higher Education
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Combination chemotherapy
US 20030216359 A1
Abstract
This invention relates to combination chemotherapy, particularly involving vitamin D or a derivative thereof. In one aspect, the invention provides a method of killing a cell by first administering to the cell vitamin D (or a derivative) and subsequently administering to the cell a cytotoxic agent. Where this strategy is applied to an intact tumor, the present invention provides a method of retarding the growth of the tumor by first administering vitamin D (or a derivative) to the tumor and subsequently administering the cytotoxic agent. A further aspect of the invention concerns a method of treating prostate cancer within a patient by co-administration of vitamin D (or a derivative) and a glucocorticoid to the patient. In yet a further aspect, the invention provides an improved method of treating a patient with vitamin-D involving the adjunctive administration of zoledronate.
Images(11)
Previous page
Next page
Claims(80)
1. A method of killing a cell within a patient comprising the steps of (a) first administering to a cell within the patient vitamin D or a derivative thereof and (b) subsequently administering at least one cytotoxic agent to the cell, wherein the cell is susceptible to said steps (a) and (b).
2. The method of claim 1, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.
3. The method of claim 2, wherein the glucocorticoid is dexamethasone.
4. The method of claim 2, wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.
5. The method of claim 1, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.
6. The method of claim 1, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.
7. The method of claim 1, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.
8. The method of claim 1, wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D3.
9. The method of claim 8, wherein the analog is Ro23-7553 or Ro24-5531.
10. The method of claim 1, wherein the vitamin D or a derivative thereof is 1,25D3.
11. The method of claim 1, wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μg and about 15 μg.
12. The method of claim 11, wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μg and about 12 μg.
13. The method of claim 1, wherein the cytotoxic agent selectively acts on cells in the G0-G1 phase of the cell cycle.
14. The method of claim 1, wherein the cytotoxic agent is a platinum-based cytotoxic agent.
15. The method of claim 1, wherein the cytotoxic agent is a glucocorticoid.
16. The method of claim 1, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.
17. The method of claim 1, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.
18. The method of claim 1, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m2.
19. The method of claim 1, wherein said cytotoxic agent is docetaxel.
20. The method of claim 1, wherein the vitamin D or a derivative thereof is 1,25D3 and wherein said cytotoxic agent is docetaxel.
21. The method of claim 1, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.
22. A method of retarding the growth of a tumor within a patient comprising the steps of (a) first administering to the tumor within the patient a vitamin D or a derivative thereof and (b) subsequently administering to the tumor at least one cytotoxic agent, wherein the cell is susceptible to said steps (a) and (b).
23. The method of claim 22, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.
24. The method of claim 23, wherein the glucocorticoid is dexamethasone.
25. The method of claim 23, wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.
26. The method of claim 22, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.
27. The method of claim 22, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.
28. The method of claim 22, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.
29. The method of claim 22, wherein the vitamin D derivative is a nonhypercalcemic analog of 1,25D3.
30. The method of claim 29, wherein the analog is Ro23-7553 or Ro24-5531.
31. The method of claim 22, wherein the vitamin D derivative is 1,25D3.
32. The method of claim 22, wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μg and about 15 μg.
33. The method of claim 32, wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μg and about 12 μg.
34. The method of claim 22, wherein the cytotoxic agent selectively acts on cells in the G0-G1 phase of the cell cycle.
35. The method of claim 22, wherein the cytotoxic agent is a platinum-based cytotoxic agent.
36. The method of claim 22, wherein the cytotoxic agent is a glucocorticoid.
37. The method of claim 22, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.
38. The method of claim 22, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.
39. The method of claim 22, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m2.
40. The method of claim 22, wherein said cytotoxic agent is docetaxel.
41. The method of claim 22, wherein said vitamin D or a derivative thereof is 1,25D3 and wherein said cytotoxic agent is docetaxel.
42. The method of claim 22, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.
43. A method of treating a human patient with vitamin D or a derivative thereof, wherein the patient has a condition responsive to vitamin D and a cytotoxic agent, comprising the steps of (a) first administering to the patient vitamin D or a derivative thereof and (b) subsequently administering to the patient at least one cytotoxic agent, wherein the dose of the vitamin D or a derivative thereof exceeds 1 μg/day.
44. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 4 μg/day.
45. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 8 μg/day.
46. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 12 μg/day.
47. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 18 μg/day.
48. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 30 μg/day.
49. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 40 μg/day.
50. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 50 μg/day.
51. The method of claim 43, wherein the vitamin D or a derivative thereof is administered orally.
52. The method of claim 43, wherein the vitamin D or a derivative thereof is administered intravenously.
53. The method of claim 43, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.
54. The method of claim 53, wherein the glucocorticoid is dexamethasone.
55. The method of claim 53, wherein the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.
56. The method of claim 43, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.
57. The method of claim 43, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.
58. The method of claim 43, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.
59. The method of claim 43, wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D3.
60. The method of claim 59, wherein the analog is Ro23-7553 or Ro24-5531.
61. The method of claim 43, wherein the vitamin D or a derivative thereof is 1,25D3.
62. The method of claim 43, wherein the cytotoxic agent selectively acts on cells in the G0-G1 phase of the cell cycle.
63. The method of claim 43, wherein the cytotoxic agent is a platinum-based cytotoxic agent.
64. The method of claim 43, wherein the cytotoxic agent is a glucocorticoid.
65. The method of claim 43, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.
66. The method of claim 43, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.
67. The method of claim 43, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m2.
68. The method of claim 43, wherein said cytotoxic agent is docetaxel.
69. The method of claim 43, wherein said vitamin D or a derivative thereof is 1,25D3 and wherein said cytotoxic agent is docetaxel.
70. The method of claim 43, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.
71. A method of treating prostate cancer within a patient in need of such treatment comprising adjunctively administering vitamin D or a derivative thereof and a glucocorticoid to the patient.
72. The method of claim 71, wherein the treatment is repeated.
73. The method of claim 71, wherein the vitamin D or a derivative thereof and glucocorticoid are administered to the patient on alternative days between 2 and 4 times a week.
74. The method of claim 71, wherein the glucocorticoid is administered to the patient prior to the administration of the vitamin D or a derivative thereof.
75. The method of claim 71, wherein the glucocorticoid is administered to the patient following the administration of the vitamin D or a derivative thereof.
76. The method of claim 71, wherein the vitamin D derivative is a nonhypercalcemic analog.
77. The method of claim 71, wherein the vitamin D derivative is 1,25D3.
78. The method of claim 71, wherein the glucocorticoid is selected from the group of glucocorticoids consisting of cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
79. The method of claim 71, wherein the glucocorticoid is dexamethasone.
80. The method of claim 71, further comprising administering at least one bisphosphonate to the cell selected from the group of bisphosphonates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.
Description
    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This patent application is a continuation of co-pending U.S. patent application Ser. No. 09/544,724, filed Apr. 6, 2000, which is a continuation-in-part of U.S. patent application Ser. No. 08/921,170, filed Aug. 29, 1997, now U.S. Pat. No. 6,087,350.
  • STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
  • [0002] This invention was made in part with Government support under Grant Number RO1-CA67267 awarded by the National Cancer Institute of the National Institutes of Health. The United States Government may have certain rights in this invention.
  • BACKGROUND OF THE INVENTION
  • [0003]
    Combating the growth of neoplastic cells and tumors has been a major focus of biological and medical research. Such research has led to the discovery of novel cytotoxic agents potentially useful in the treatment of neoplastic disease. Examples of cytotoxic agents commonly employed in chemotherapy include anti-metabolic agents interfering with microtubule formation, alkylating agents, platinum-based agents, anthracyclines, antibiotic agents, topoisomerase inhibitors, and other agents.
  • [0004]
    Aside from merely identifying potential chemotherapeutic agents, cancer research has led to an increased understanding of the mechanisms by which these agents act upon neoplastic cells, as well as on other cells. For example, cholecalciferol (vitamin D) can effect differentiation and reduce proliferation of several cell types cells both in vitro and in vivo. The active metabolite of vitamin D (1,25-dihydroxycholecalciferol (hereinafter “1,25D3”)) and analogs (e.g., 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553), 1,25-dihydroxy-16-ene-23-yne-26, 27-hexafluoro-19-nor-cholecalciferol (Ro25-6760), etc.) mediate significant in vitro and in vivo anti-tumor activity by retarding the growth of established tumors and preventing tumor induction (Colston et al., Lancet, 1, 188 (1989); Belleli et al., Carcinogenesis, 13, 2293 (1992); McElwain et al., Mol. Cell. Diff., 3, 31-50 (1995); Clark et al., J. Cancer Res. Clin. Oncol., 118, 190 (1992); Zhou et al., Blood, 74, 82-93 (1989)). In addition to retarding neoplastic growth, 1,25D3 induces a G0/G1-S phase block in the cell cycle (Godyn et al, Cell Proliferation, 27, 37-46 (1994); Rigby et al., J. Immunol., 135, 2279-86 (1985); Elstner et al., Cancer Res., 55, 2822-30 (1995); Wang et al., Cancer Res., 56, 264-67 (1996)). These properties have led to the successful use of 1,25D3 to treat neoplastic tumors (see Cunningham et al., Br. J. Cancer, 63, 4673 (1991); Mackie et al., Lancet, 342, 172 (1993), Bower et al., Proc. Am. Assoc. Cancer. Res., 32, 1257 (1991)).
  • [0005]
    In addition to its antineoplastic and cell-cycle blocking effects, 1,25D3 treatment can lead to hypercalcemia. As a result, 1,25D3 is typically administered for therapeutic applications (e.g., metabolic bone disease) at relatively low doses (e.g., about 1 μg/day to about 2 μg/day per patient) long term. To mitigate the effects of hypercalcemia, analogs have been developed which retain antiproliferative activity without inducing hypercalcemia. (See, e.g., Zhou et al., Blood, 73, 75 (1991); Binderup et al., Biochem. Pharmacol., 42, 1569 (1991); Binderup et al., page 192 in Proceedings of the 8th Workshop on Vitamin D, Paris France (Norman, A. et al., Eds., Walter de Gruyter, Berlin, (1991))). Many of these synthetic analogs are more potent than 1,25D3 in inhibiting neoplastic growth (for a review of many such analogs, see Calverley et al., “Vitamin D” in Antitumor Steroids (Blickenstaff, R. T., Ed., Academic Press, Orlando (1992))).
  • [0006]
    The platinum-based agents are widely utilized in chemotherapeutic applications. For example, cisplatin kills tumor cells via formation of covalent, cross- or intrastrand DNA adducts (Sherman et al. Chem. Rev., 87, 1153-81 (1987); Chu, J. Biol. Chem., 269, 787-90 (1994)). Treatment with such platinum-based agents thereby leads to the inhibition of DNA synthesis (Howle et al., Biochem. Pharmacol., 19, 2757-62 (1970); Salles et al., Biochem. Biophys. Res. Commun., 112, 555-63 (1983)). Thus, cells actively synthesizing DNA are highly sensitive to cisplatin (Roberts et al., Prog. Nucl. Acid Res. Mol. Biol., 22, 71-133 (1979); Pinto et al., Proc. Nat. Acad. Sci. (Wash) 82, 4616-19 (1985)). Such cells generally experience a growth arrest in G2 and eventually undergo apoptosis. This apoptotic effect is observed at drug concentrations insufficient to inhibit DNA synthesis (Sorenson et al., J. Natl. Cancer Inst., 82, 749-55 (1990)), suggesting that platinum agents act on neoplastic cells via multiple mechanisms. Some cells also demonstrate increased platinum sensitivity when in the G1 phase of the cell cycle (Krishnaswamy et al., Mutation Res., 293, 161-72 (1993); Donaldson et al., Int. J. Cancer, 57, 847-55 (1994)). Upon release from G0/G1-S block, such cells remain maximally sensitized through the remainder of the cell cycle.
  • [0007]
    Other chemotherapeutic agents act by different mechanisms. For example, agents interfering with microtubule formation (e.g., vincristine, vinblastine, paclitaxel, docetaxel, etc.) act against neoplastic cells by interfering with proper formation of the mitotic spindle apparatus (see, e.g., Manfredi et al., Pharmacol. Ther., 25, 83-125 (1984)). Thus, agents interfering with microtubule formation mainly act during the mitotic phase of the cell cycle (Schiff et al., Proc. Nat. Acad. Sci. U.S.A., 77, 1561-65 (1980); Fuchs et al., Cancer Treat. Rep., 62, 1219-22 (1978); Lopes et al., Cancer Chemother. Pharmacol., 32, 235-42 (1993)). Antimetabolites act on various enzymatic pathways in growing cells. For example, methotrexate (MTX) is a folic acid analog which inhibits dihydrofolate reductase. As a result, it blocks the synthesis of thymidylate and purines required for DNA synthesis. Thus, the primary impact of MTX is in the S phase of the cell cycle, but it can also impact RNA synthesis in G1 and G2 (Olsen, J. Am. Acad. Dermatol., 25, 306-18 (1991)). Of course, other cytotoxic agents can also be employed (e.g., taxanes such as docetaxel (e.g., TAXATERE®)).
  • [0008]
    Because of the differences in the biological mechanisms of various cytotoxic agents, protocols involving combinations of different cytotoxic agents have been attempted (e.g., Jekunen et al., Br. J. Cancer, 69, 299-306 (1994); Yeh et al., Life Sciences, 54, 431-35 (1994)). Combination treatment protocols aim to increase the efficacy of cytopathic protocols by using compatible cytotoxic agents. In turn, the possibility that sufficient antineoplastic activity can be achieved from a given combination of cytotoxic agents presents the possibility of reducing the dosage of individual cytotoxic agents to minimize harmful side effects. In part because the various cytotoxic agents act during different phases of the cell cycle, the success of combination protocols frequently depends upon the order of drug application (e.g., Jekunen et al., supra; Studzinski et al, Cancer Res., 51, 3451 (1991)).
  • [0009]
    There have been attempts to develop combination drug protocols based, in part, on vitamin D and derivatives thereof. For example, the inhibitory effect of the concurrent administration of 1,25D3 and platinum drugs on the growth of neoplastic cells has been studied (Saunders et al., Gynecol. Oncol., 51, 155-59 (1993); Cho et al., Cancer Res., 51, 2848-53 (1991)), and similar studies have focused on concurrent combinations of 1,25D3 and other cytotoxic agents (Tanaka et al., Clin. Orthopaed. Rel. Res., 247, 290-96 (1989)). The results of these studies, however, have been less than satisfactory. In particular, the optimal sequence of drug administration has not been achieved. Moreover, the application of these approaches in therapy would require the long-term application of high doses of 1,25D3 in some protocols, which, as mentioned, can precipitate significant side effects. Thus, there remains a need for an improved method of enhancing the efficacy of chemotherapeutic agents, particularly a need for an improved combination therapy, especially involving vitamin D and derivatives thereof.
  • BRIEF SUMMARY OF THE INVENTION
  • [0010]
    This invention relates to combination chemotherapy, particularly involving vitamin D or a derivative thereof. In one aspect, the invention provides a method of killing a cell by first administering to the cell vitamin D (or a derivative) and subsequently administering to the cell a cytotoxic agent. Where this strategy is applied to an intact tumor, the present invention provides a method of retarding the growth of the tumor by first administering vitamin D (or a derivative) to the tumor and subsequently administering the cytotoxic agent. A further aspect of the invention concerns a method of treating prostate cancer within a patient by co-administration of vitamin D (or a derivative) and a glucocorticoid to the patient. In yet a further aspect, the invention provides an improved method of treating a patient with vitamin-D involving the adjunctive administration of zoledronate.
  • [0011]
    In some applications, the inventive method is a useful therapy, particularly in the treatment of neoplastic or cancerous diseases. In other applications, the present invention provides a tool for further research pertaining to subjects including neoplastic cell growth, the control and regulation of the cell cycle, and the mechanism and efficacy of cytotoxicity and chemotherapy. In this respect, the inventive method is useful for the development of more refined therapies. The invention can best be understood with reference to the following detailed description.
  • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • [0012]
    In one embodiment, the invention provides a method of killing a cell (e.g., a targeted cell) by first administering vitamin D (or a derivative) to the cell and subsequently administering a cytotoxic agent to the cell. Any period of pretreatment can be employed in the inventive method; the exact period of pretreatment will vary depending upon the application for the inventive method. For example, in therapeutic applications, such pretreatment can be for as little as about a day to as long as about 5 days or more; more preferably, the pretreatment period is between about 2 and about 4 days (e.g., about 3 days). Following pretreatment, the inventive method involves administering a cytotoxic agent. However, in a preferred embodiment, a glucocorticoid (e.g., cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, etc.), diphenhydramine, rantidine, antiemetic-ondasteron, or ganistron can be adjunctively administered, and such agents can be administered with vitamin D (or a derivative). The cytotoxic agent can be administered either alone or in combination with continued administration of vitamin D (or a derivative) following pretreatment. While, typically, treatment ceases upon administration of the cytotoxic agent, it can be administered continuously for a period of time (e.g., periodically over several days) as desired.
  • [0013]
    The cell can be solitary and isolated from other like cells (such as a single cell in culture or a metastatic or disseminated neoplastic cell in vivo), or the cell can be a member of a collection of cells (e.g., within a tumor). Preferably, the cell is a neoplastic cell (e.g., a type of cell exhibiting uncontrolled proliferation, such as cancerous or transformed cells). Neoplastic cells can be isolated (e.g., a single cell in culture or a metastatic or disseminated neoplastic cell in vivo) or present in an agglomeration, either homogeneously or in heterogeneous combination with other cell types (neoplastic or otherwise) in a tumor or other collection of cells. Where the cell is within a tumor, the present invention provides a method of retarding the growth of the tumor by first administering vitamin D (or a derivative) to the tumor and subsequently administering the cytotoxic agent to the tumor. By virtue of the cytopathic effect on individual cells, the inventive method can reduce or substantially eliminate the number of cells added to the tumor mass over time. Preferably, the inventive method effects a reduction in the number of cells within a tumor, and, most preferably, the method leads to the partial or complete destruction of the tumor (e.g., via killing a portion or substantially all of the cells within the tumor).
  • [0014]
    Where the cell is associated with a neoplastic disorder within a patient (e.g., a human), the invention provides a method of treating the patient by first administering vitamin D (or a derivative) to the patient and subsequently administering the cytotoxic agent to the patient. This approach is effective in treating mammals bearing intact or disseminated cancer. For example, where the cells are disseminated cells (e.g., metastatic neoplasia), the cytopathic effects of the inventive method can reduce or substantially eliminate the potential for further spread of neoplastic cells throughout the patient, thereby also reducing or minimizing the probability that such cells will proliferate to form novel tumors within the patient. Furthermore, by retarding the growth of tumors including neoplastic cells, the inventive method reduces the likelihood that cells from such tumors will eventually metastasize or disseminate. Of course, when the inventive method achieves actual reduction in tumor size (and especially elimination of the tumor), the method attenuates the pathogenic effects of such tumors within the patient. Another application is in high-dose chemotherapy requiring bone marrow transplant or reconstruction (e.g., to treat leukemic disorders) to reduce the likelihood that neoplastic cells will persist or successfully regrow.
  • [0015]
    In many instances, the pretreatment of cells or tumors with vitamin D (or a derivative) before treatment with the cytotoxic agent effects an additive and often synergistic degree of cell death. In this context, if the effect of two compounds administered together in vitro (at a given concentration) is greater than the sum of the effects of each compound administered individually (at the same concentration), then the two compounds are considered to act synergistically. Such synergy is often achieved with cytotoxic agents able to act against cells in the G0-G1 phase of the cell cycle, and such cytotoxic agents are preferred for use in the inventive methods. While any such cytotoxic agent can be employed (as discussed herein), preferred cytotoxic agents are platinum-based agents (e.g., cisplatin, carboplatin, etc.). Without being bound by any particular theory, it is believed that the inventive method effects cytotoxicity of neoplastic cells by inducing a G0/G1-S phase block in the cell cycle, as mentioned herein. The cells are sensitized to cytotoxic agents able to act on cells in such a blocked stage. Alternatively, synchronization of the release of the cells from the block can render them collectively sensitive to the effects of agents acting later in the cell cycle.
  • [0016]
    As an alternative to vitamin D, any derivative thereof suitable for potentiating the cytotoxic effect of chemotherapeutic agents can by used within the context of the inventive method, many of which are known in the art (see, e.g., Calverley et al., supra). One preferred derivative is its natural metabolite (1,25D3). However, many vitamin D analogs have greater antitumor activity than the native metabolite; thus the vitamin D derivative can be such an analog of 1,25D3. Furthermore, where the inventive method is used for therapeutic applications, the derivative can be a nonhypercalcemic analog of 1,25D3, as such analogs reduce or substantially eliminate the hypercalcemic side effects of vitamin D-based therapy. For example, the analog can be Ro23-7553, Ro24-5531, or another analog. In some embodiments, other agents that attenuate (e.g., deactivate) MAP kinase, specifically by inducing MAPK phosphatase, can be used as equivalents of vitamin D (or a derivative).
  • [0017]
    Pursuant the inventive method, the vitamin D (or a derivative) can be provided to the cells or tumors in any suitable manner, which will, of course, depend upon the desired application for the inventive method. Thus, for example, for in vitro applications, vitamin D (or a derivative) can be added to the culture medium (e.g., mixed initially with the medium or added over time). For in vivo applications, vitamin D (or a derivative) can be mixed into an appropriate vehicle for delivery to the cell or tumor. Thus, for systemic delivery, vitamin D (or a derivative) can be supplied by subcutaneous injection, intravenously, orally, or by other suitable means. Of course, vitamin D (or a derivative) can be provided more directly to the tumor (e.g., by application of a salve or cream comprising vitamin D (or a derivative) to a tumor, by injection of a solution comprising vitamin D (or a derivative) into a tumor, etc.).
  • [0018]
    The dose of vitamin D (or a derivative) provided to the cells can vary depending upon the desired application. In research, for example, the dose can vary considerably, as dose-response analysis might be a parameter in a given study. For therapeutic applications, because the pretreatment period can be quite brief in comparison with standard vitamin D-based therapies, higher than typical doses (as discussed above) of vitamin D (or a derivative) can be employed in the inventive method without a substantial risk of hypercalcemia. Thus, for example, in a human patient, as little as 1 μg/day of vitamin D (or a derivative) (which as mentioned above, is within the normal dosage for 1,25D3) can be supplied to a patient undergoing treatment, while the maximal amount can be as high as about 20 μg/day (or even higher in some larger patients). Preferably, between about 4 μg/day and about 15 μg/day (e.g., between about 7 μg/day and about 12 μg/day) of vitamin D (or a derivative) is delivered to the patient. Typically, the amount of vitamin D (or a derivative) supplied will not be so great as to pose a significant risk of inducing hypercalcemia or provoking other toxic side effects. Hence, where non-hypercalcemic vitamin D derivatives are used, higher amounts still can be employed. Thus, 30 μg/day or more (e.g., about 40 μg/day or even 50 μg/day or more) non-hypercalcemic vitamin D derivative can be delivered to a human patient during pretreatment in accordance with the inventive method. Of course, the desired dose of vitamin D (or a derivative) will depend upon the size of the patient and the mode and timing of delivery. Vitamin D (or a derivative) can be delivered once a day, or several times a day, as desired, or it can be delivered discontinuously (e.g., every other day, or every third day). The determination of such doses and schedules is well within the ordinary skill in the art.
  • [0019]
    Any cytotoxic agent can be employed in the context of the invention; as mentioned, many cytotoxic agents suitable for chemotherapy are known in the art. Such an agent can be, for example, any compound mediating cell death by any mechanism including, but not limited to, inhibition of metabolism or DNA synthesis, interference with cytoskeletal organization, destabilization or chemical modification of DNA, apoptosis, etc. For example, the cytotoxic agent can be an antimetabolite (e.g., 5-flourouricil (5-FU), methotrexate (MTX), fludarabine, etc.), an anti-microtubule agent (e.g., vincristine, vinblastine, taxanes (such as paclitaxel and docetaxel), etc.), an alkylating agent (e.g., cyclophasphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin-C), topoisomerase inhibitors (e.g., etoposide, camptothecins, etc.), or other cytotoxic agents (e.g., dexamethasone). The choice of cytotoxic agent depends upon the application of the inventive method. For research, any potential cytotoxic agent (even a novel cytotoxic agent) can be employed to study the effect of the toxin on cells or tumors pretreated with vitamin D (or a derivative). For therapeutic applications, the selection of a suitable cytotoxic agent will often depend upon parameters unique to a patient; however, selecting a regimen of cytotoxins for a given chemotherapeutic protocol is within the skill of the art.
  • [0020]
    For in vivo application, the appropriate dose of a given cytotoxic agent depends on the agent and its formulation, and it is well within the ordinary skill of the art to optimize dosage and formulation for a given patient. Thus, for example, such agents can be formulated for administration via oral, subcutaneous, parenteral, submucosal, intraveneous, or other suitable routes using standard methods of formulation. For example, carboplatin can be administered at daily dosages calculated to achieve an AUC (“area under the curve”) of from about 4 to about 15 (such as from about 5 to about 12), or even from about 6 to about 10. Typically, AUC is calculated using the Calvert formula, based on the glomerular filtration rate of creatinine (e.g., assessed by analyzing a plasma sample) (see, e.g., Martino et al., Anticancer Res., 19(6C), 5587-91 (1999)). Paclitaxel can be employed at concentrations ranging from about 50 mg/m2 to about 100 mg/m2 (e.g., about 80 mg/m2). Where dexamethasone is employed, it can be used within patients at doses ranging between about 1 mg to about 10 mg (e.g., from about 2 mg to about 8 mg), and more particularly from about 4 mg to about 6 mg, particularly where the patient is human.
  • [0021]
    Another embodiment of the invention provides a method of treating prostate cancer within a patient by adjunctively administrating vitamin D (or a derivative) and a glucocorticoid to the patient. Any vitamin D derivative and glucocorticoid can be employed in accordance with this aspect of the invention, many of which are discussed elsewhere herein and others are generally known in the art. Moreover, vitamin D (or a derivative) and the glucocorticoid are delivered to the patient by any appropriate method, some of which are set forth herein. Thus, they can be formulated into suitable preparations and delivered subcutaneously, intravenously, orally, etc., as appropriate. Also, for example, the glucocorticoid is administered to the patient concurrently, prior to, or following the administration of vitamin D (or a derivative). One effective dosing schedule is to delver between about 8 μg and about 12 μg vitamin D (or a derivative) daily on alternative days (e.g., between 2 and 4 days a week, such as Mon-Wed-Fri or Tues-Thus-Sat, etc.), and also between about 1 mg and 10 mg dexamethasone (e.g., about 5 mg) to a human patient also on alternative days. In such a regimen, the alternative days on which vitamin D (or a derivative) and on which the glucocorticoid are administered can be different, although preferably they are administered on the same days. Even more preferably, the glucocorticoid is administered once, by itself, prior to concurrent treatment. Of course, the treatment can continue for any desirable length of time, and it can be repeated, as appropriate to achieve the desired end results. Such results can include the attenuation of the progression of the prostate cancer, shrinkage of such tumors, or, desirably, remission of all symptoms. However, any degree of effect is considered a successful application of this method. A convenient method of assessing the efficacy of the method is to note the change in the concentration of prostate-specific antigen (PSA) within a patient. Typically, such a response is gauged by measuring the PSA levels over a period of time of about 6 weeks. Desirably, the method results in at least about a 50% decrease in PSA levels after 6 weeks of application, and more desirably at least about 80% reduction in PSA. Of course, the most desirable outcome is for the PSA levels to decrease to about normal levels (e.g., less than about 4 ng/ml for at least three successive measurements in a non-prostatectomized individual or less than about 0.2 ng/ml in a prostatectomized individual).
  • [0022]
    In all aspects of the invention that involve in vivo application, preferably the method is employed to minimize the hypercalcemic properties of vitamin D. One manner of accomplishing this is to employ a nonhypercalcemic analog, such as those discussed above. Alternatively, or in conjunction with the use of such analogs, an agent that mitigates hypercalcemia can be adjunctively delivered to the patient. While any such agent can be employed, bisphosphonates (e.g., alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, zoledronate, etc.) are preferred agents for adjunctive administration. Such agents can be administered in any suitable manner to mitigate hypercalcemia. Thus, they can be formulated into suitable preparations and delivered subcutaneously, intravenously, orally, etc., as appropriate. Also, such agents can be administered concurrently, prior to, or subsequent to vitamin D (or a derivative). The dosage of such agents will, of course, vary with the potency of the compounds and also to mitigate any unwanted side effects. Thus, for example, for administration to human patients, the dosage of bisphosphonates can vary between about 1 mg/day and 500 mg/day (e.g., between about 5 mg/day and 100 mg/day), such as between about 10 mg/day and about 50 mg/day, or even between about 30 mg/day and about 40 mg day, depending on the potency of the bisphosphonates. Generally, it is preferred to employ a more potent bisphosphonate, as less of the agent need be employed to achieve the antihypercalcemic effects. Thus, a most preferred bisphosphonate is zoledronate, as it is effective even at very low doses (e.g., between about 0.5 mg day and about 2 mg/day in human patients, or between about 5 μg/kg to about 25 μg/kg body weight).
  • [0023]
    Indeed, in another aspect, the invention provides an improved method of employing vitamin D (or a derivative) therapeutically by adjunctively administering zoledronate. The zoledronate can be delivered as an adjunct in conjunction with any protocol in which vitamin D (or a derivative) is employed, such as those discussed herein or otherwise employed. As an adjunct, the zoledronate can be delivered in any desired regimen (several times a day, daily, weekly, etc.), as desired. Preferably, the zoledronate is delivered as a pretreatment, e.g., several hours to several days before treatment with vitamin D (or a derivative) commences. More preferably, the zolendronate is adjunctively administered in an amount sufficient to mitigate the antihypercalcemic effects of vitamin D (or a derivative).
  • [0024]
    While one of skill in the art is fully able to practice the instant invention upon reading the foregoing detailed description, the following examples will help elucidate some of its features. Of course, as these examples are presented for purely illustrative purposes, they should not be used to construe the scope of the invention in a limited manner, but rather should be seen as expanding upon the foregoing description of the invention as a whole.
  • EXAMPLE 1
  • [0025]
    This example explains the materials and general methods employed in the following examples.
  • [0026]
    Inbred female C3H/HeJ mice age 6-10 weeks were obtained from Jackson Laboratories. The mice were virus antibody-free, age and weight-matched for experimental use, and fed a balanced rodent diet.
  • [0027]
    SCCVII/SF cells—a murine, rapidly growing, non-metastasizing squamous tumor line—were maintained in vivo in C3H/HeJ mice as described previously (McElwain et al., Mol. Cell. Diff., 3, 31-50 (1995)) by s.c. inoculation of 5×105 log-phase tissue culture cells in the right flank of the animal. The SCCVII/SF cell line was maintained in vitro in RPMI-1640 supplemented with 12.5% inactivated fetal calf serum (FCS) and 1% penicillin-streptomycin sulfate.
  • [0028]
    1,25D3 and its non-hypercalcemic analog, Ro23-7553, were initially stored in pure powder form in a sealed light-protective vessel at 4° C. For use, each drug was reconstituted in 100% ethyl alcohol and maintained as described (McElwain et al., Mol. Cell. Diff., 3, 31-50 (1995)). The cytotoxic agents (carboplatin, cisplatin, and paclitaxel) were diluted in 0.9% saline and were injected i.p. at various doses in a total volume of 0.2 ml, during the experimental protocols.
  • [0029]
    The in vitro cytotoxicity of drug on tumor cells was determined via the in vitro clonogenic assay (McElwain et al., Mol. Cell. Diff., 3, 31-50 (1995)) with minor modifications as described herein. Briefly, murine SCCVII/SF cells were pre-treated with either 2 nM or 4 nM 1,25D3 or Ro23-7553. While 1,25D3 or Ro23-7553 are not stable for long periods in tissue culture media, anti-proliferative effects are observed at 24 hr, 48 hr and 7 day incubation times (McElwain et al., supra). After 48 hours incubation with 1,25D3 or Ro23-7553, cells were treated for 2 hours with varying concentrations of cytotoxic agent, washed with RPMI 1640 plus FCS, and plated in various dilutions in 6-well tissue culture plates. Following a 7 day incubation at 37° C. in 5% CO2, monolayers were washed with saline, fixed with 100% methanol, and stained with 10% Giemsa; colonies were counted under light microscopy. The surviving fraction was calculated by dividing the cloning efficiency of treated cells by the cloning efficiency of untreated controls.
  • [0030]
    The effect of 1,25D3 or Ro23-7553 alone and/or in combination with various cytotoxic agents on tumor cells in vivo was determined by a modification of the in vivo excision clonogenic tumor cell survival assay (Johnson et al., Cancer Chemother. Pharmacol., 32, 339-46 (1993)). Briefly, SCCVII/SF tumor bearing animals at 14 days post implantation were treated i.p. for 3 days with 1,25D3 or Ro23-7553 at either 0.5 mg/kg body weight/day or at varying doses of 0.03125-0.5 mg/kg body weight/day. On day 3, animals also received an i.p. dose of either 6 mg/kg body weight or varying doses of 1-6 mg/kg body weight of cytotoxic agent. After 24 hours, aliquots of minced tumor were enzymatically dissociated for 60 min at room temperature with a mixture of type I collagenase (37.5 mg/ml), DNAse (55 mg/ml) and EDTA (1%). Viable tumor cells (determined by trypan blue staining) were then plated at various dilutions. After 7 days incubation, colonies were counted, and numbers of clonogenic cells per gram of tumor were counted. The mean±standard deviation (SD) cell yield, cloning efficiency, and number of clonogenic cells for control (no treatment) tumors (n=40) averaged 139.4±38.2×106 viable tumor cells/g tumor, 27.0±0.56%, and 37.5±13.3×106 clonogenic tumor cells/g tumor, respectively. The surviving fraction per gram of tumor is defined as the number of clonogenic tumor cells per gram of treated tumor divided by the number of clonogenic tumor cells per gram of control (untreated) tumor. This assay is an accurate measure of in vivo anti-tumor activity; a surviving fraction less than 0.1 correlates with an actual decrease in tumor volume and an increase in tumor regrowth delay (Braunschweiger et al., Cancer Res., 48, 6011-16 (1988); Braunschweiger et al., Cancer Res., 51, 5454-60 (1991)).
  • [0031]
    The effect of 1,25D3 or Ro23-7553 alone and/or in combination with various cytotoxic agents on tumor cells in vivo was further assayed by measuring the delay of tumor growth (tumor regrowth assay). SCCVII/SF tumor cells (5×105) were inoculated s.c. into the flank of the leg of C3H/HeJ mice. On day 9 post implantation, as the tumors were palpable (approximately 5×5 mm), animals were randomized for treatment with low dose i.p. Ro23-7553 (0.214 μg/kg body weight/day) or 1,25D3 (0.2 μg/mouse) using a micro-osmotic pump for continuous delivery over seven days. After 7 days, 6 mg/kg body weight cytotoxic agent was injected i.p. Control animals received either treatment alone or no treatment. Control (no treatment) animals were given injection of vehicle (PBS) alone or sham pumps were implanted. Tumor growth was assessed by measuring the tumor diameter with calipers three times weekly. Tumor volumes were calculated by the formula: volume=length×(width2)/2. Post-treatment volumes were expressed as a fraction of pretreatment volume at the time of initial treatment. Tumor regrowth delay was calculated as the mean±standard deviation of the difference in time for treated and control tumor volumes to reach 4 times the pretreatment volume.
  • EXAMPLE 2
  • [0032]
    This example demonstrates the potential for sensitizing tumor cells to the effects of conventional cytotoxic cisplatin therapy by pretreatment with a vitamin D derivative.
  • [0033]
    Between 0.2 μg/ml and 0.8 μg/ml cisplatin and Ro23-7553 were tested alone and in combination using the in vitro clonogenic assay for the SCCVII/SF tumor cell line as described above. It was observed that pretreatment of cells with both 2 nM and 4 nM Ro23-7553 significantly enhanced clonogenic cell kill when compared to cisplatin alone or in concurrent administration (i.e., no pretreatment) of cisplatin in combination with Ro23-7553 (p<0.001 ANOVA). Significant enhancement of cisplatin-mediated cytotoxicity was observed even at low doses of cisplatin.
  • EXAMPLE 3
  • [0034]
    This example demonstrates the enhancement of in vivo cisplatin-mediated anti-tumor activity by pretreatment with a vitamin D derivative.
  • [0035]
    The excision clonogenic kill assay was employed wherein SCCVII/SF tumor bearing animals at 14 days post implantation were treated i.p. for 3 days with 0.5 mg/kg body weight/day of Ro23-7553. On the third day animals received varying doses of cisplatin. After 24 hours, tumors were harvested, dissociated, and plated for a 7 day incubation. It was observed that pretreatment for 3 days with the Ro23-7553 before cisplatin resulted in a significant enhancement of clonogenic cell kill when compared to animals treated with cisplatin or Ro23-7553 alone (p<0.001 ANOVA). A significant increase in clonogenic tumor cell kill was observed at each cisplatin dose tested as compared to cisplatin alone.
  • [0036]
    To determine the effect of varying the Ro23-7553 dose in this assay, SCC tumor-bearing mice were treated daily for 3 days with from 0.03125 mg/kg body weight/day to 0.5 mg/kg body weight/day Ro23-7553. On day 3, cisplatin was administered at 6 mg/kg body weight. It was observed that Ro23-7553 was capable of significantly enhancing cisplatin-mediated tumor cell kill even at the lowest doses tested as compared to cisplatin or Ro23-7553 alone (p<0.01 ANOVA). No animals in either experimental approach became hypercalcemic at any of the Ro23-7553 doses.
  • EXAMPLE 4
  • [0037]
    This example demonstrates the enhancement of in vivo cisplatin-mediated anti-tumor activity by pretreatment with a vitamin D derivative.
  • [0038]
    The tumor regrowth assay was employed wherein SCCVII/SF tumor-bearing mice (day 9 post implantation) were treated with Ro23-7553 administered continuously. At the end of Ro23-7553 administration, cisplatin was injected i.p. at 6 mg/kg body weight. Control (no treatment) or single treatment animals were injected with vehicle (PBS) or implanted with sham pumps depending on the treatment group. All animals experienced a significant decrease in fractional tumor volume when pre-treated with Ro23-7553 before cisplatin as compared to treatment with either agent alone (p<0.001 ANOVA). When tumor regrowth delay (mean±SD of the difference in time for treated and control tumors to reach 4× pretreatment size) was examined, a significant increase was observed in animals treated with Ro23-7553 plus cisplatin as compared either to cisplatin or Ro23-7553 alone (see Table 1)
    TABLE 1
    Effect of Ro23-7553 and Cisplatin on Tumor Regrowth Delay
    Treatment Tumor Regrowth Delay
    Ro23-7553 1.8 ± 0.8
    Cisplatin 4.4 ± 0.3
    Ro23-7553/cisplatin 7.7 ± 0.4
  • EXAMPLE 5
  • [0039]
    This example demonstrates the potential for sensitizing tumor cells to the effects of cisplatin therapy by pretreatment with a vitamin D derivative and dexamethasone.
  • [0040]
    SCC cells were incubated with dexamaethasone, 1,25D3, and /or cisplatin, and cell viability was determined via trypan blue exclusion. It was observed that pretreatment with dexamaethasone and 1,25D3 followed by cisplatin resulted in greater growth inhibition than treatment with any agent alone or pretreatment with 1,25D3 followed by cisplatin. These results demonstrate that pretreatment with a vitamin D derivative and dexamethasone enhances the antitumor effect of cisplatin.
  • EXAMPLE 6
  • [0041]
    This example demonstrates the potential for sensitizing tumor cells to the effects of cisplatin therapy by pretreatment with a vitamin D derivative and dexamethasone in vivo.
  • [0042]
    SC tumor-bearing mice were treated with dexamethasone on days 0-3, 1,25D3 on days 1-3, and/or cisplatin on day 3. Greater antiproliferative activity was observed for the triply-treated animals than for animals treated with dexamethasone followed by cisplatin (p<0.003 using the Mann-Whitley test) or with 1,25D3 followed by cisplatin (p<0.05 using the Mann-Whitley test). These results demonstrate that pretreatment with a vitamin D derivative and dexamethasone enhances the antitumor effect of cisplatin.
  • EXAMPLE 7
  • [0043]
    This example demonstrates that vitamin D derivatives can up-regulate a MAPK phosphatase.
  • [0044]
    SCC cells were treated in vitro with 10 nM 1,25D3, and untreated cells served as a control. The level of phosphorylated MAPK was assessed at 24 and 48 hours post treatment. Using Western Blot analysis, the amounts of MAPK, MEK (the kinase responsible for phosphorylating MAPK), MKP-1 (a MAPK-specific phosphatase), and growth factor receptors (EGF, PDGF, and IGF1 growth factor receptors) were assessed as well. Additionally, the activity level of MEK was assessed by quantitative in vitro kinase assays.
  • [0045]
    Cells treated with 1,25D3 had less phosphorylated MAPK than untreated cells, but the amount of MAPK protein was not affected. The treated cells had slightly less MEK protein present, but the MEK activity profile was not significantly different from the untreated cells. Additionally, the treated cells had significantly higher amounts of EGF, PDGF, and IGF1 growth factor receptors than untreated cells, as well as higher amounts of MKP-1.
  • [0046]
    The results indicate that 1,25D3 does not inhibit MAPK by inhibiting the upstream mitogenic signal from growth factor receptors, but that it may inhibit this protein by up-regulating MKP-1.
  • EXAMPLE 8
  • [0047]
    This example demonstrates the potential for sensitizing tumor cells to the effects of conventional cytotoxic carboplatin therapy by pretreatment with a vitamin D derivative.
  • [0048]
    Carboplatin and 1,25D3 were tested alone and in combination using the in vitro clonogenic assay. It was observed that pretreatment of cells with 2 nM 1,25D3 for 48 hours significantly enhanced clonogenic cell kill when compared to carboplatin alone or in concurrent administration (i.e., no pretreatment) of carboplatin in combination with 1,25D3 (p<0.001 ANOVA).
  • EXAMPLE 9
  • [0049]
    This example demonstrates the enhancement of in vivo carboplatin-mediated anti-tumor activity by pretreatment with a vitamin D derivative.
  • [0050]
    The excision clonogenic kill assay was employed wherein SCCVII/SF tumor bearing animals at 14 days post implantation were treated i.p. for 3 days with 0.5 mg/kg body weight/day of 1,25D3. On the third day animals received varying doses of carboplatin (between 25 mg/kg body weight and 100 mg/kg body weight). After 24 hours, tumors were harvested, dissociated, and plated for a 7 day incubation. It was observed that pretreatment for 3 days with 1,25D3 before carboplatin resulted in a significant enhancement of clonogenic cell kill when compared to animals treated with carboplatin or 1,25D3 alone (p<0.001 ANOVA). A significant increase in clonogenic tumor cell kill was observed at each carboplatin dose tested.
  • [0051]
    In a second experiment, the excision clonogenic kill assay was employed wherein the SCCVII/SF tumor bearing animals at 14 days post implantation were treated i.p. for 3 days with 1,25D3 at varying doses. On the third day, animals received 50 mg/kg body weight/day carboplatin. After 24 hours, tumors were harvested, dissociated, and plated for a 7 day incubation. It was observed that pretreatment with 1,25D3 before carboplatin resulted in a significant enhancement of clonogenic cell even at the lowest doses of 1,25D3. A significant increase in clonogenic tumor cell kill was observed at each carboplatin dose tested as compared to carboplatin alone (p<0.001 ANOVA). No animals became hypercalcemic at any of the 1,25D3 doses tested.
  • EXAMPLE 10
  • [0052]
    This example demonstrates the potential for sensitizing tumor cells to the effects of conventional cytotoxic paclitaxel by pretreatment with a vitamin D analog.
  • [0053]
    Paclitaxel and 1,25D3 were tested alone and in combination using the in vitro clonogenic assay as described above. It was observed that pretreatment of cells with 1,25D3 significantly enhanced clonogenic cell kill when compared to 1,25D3 (p<0.001 ANOVA). It was also observed that concurrent administration of 1,25D3 and paclitaxel did not result in an enhancement of clonogenic cell kill over paclitaxel alone.
  • EXAMPLE 11
  • [0054]
    This example demonstrates the enhancement of paclitaxel-mediated in vivo anti-tumor activity by pretreatment with 1,25D3.
  • [0055]
    The excision clonogenic kill assay was employed wherein SCCVII/SF tumor bearing animals at 11 days post implantation were treated i.p. for 3 days with 0.2 μg/day of 1,25D3. On the third day, animals received varying doses of paclitaxel. After 24 hours, tumors were harvested, dissociated, and plated for a 7 day incubation. It was observed that pretreatment for 3 days with 1,25D3 before paclitaxel, at all doses, resulted in a significant enhancement of clonogenic cell kill when compared to animals treated with paclitaxel alone (p<0.001 ANOVA). A significant increase in clonogenic tumor cell kill also was observed at each paclitaxel dose tested as compared to paclitaxel alone. No animals became hypercalcemic during these treatments.
  • EXAMPLE 12
  • [0056]
    This example demonstrates the enhancement of in vivo paclitaxel-mediated anti-tumor activity by pretreatment with 1,25D3.
  • [0057]
    The tumor regrowth assay was employed wherein SCCVII/SF tumor-bearing mice (day 7 post implantation) were treated with 0.2 μg/mouse 1,25D3 administered continuously for between two and eight days. At the end of 1,25D3 administration, paclitaxel was injected i.p. at 40 mg/kg body weight. Control (no treatment) or single treatment animals were injected with vehicle (PBS) or implanted with sham pumps depending on the treatment group. All animals experienced a significant decrease in fractional tumor volume when pre-treated with 1,25D3 before paclitaxel as compared to treatment with either agent alone (p<0.001 ANOVA).
  • EXAMPLE 13
  • [0058]
    This is an example of a clinical dosing schedule for treatment with carboplatin and 1,25D3 in accordance with the inventive method.
  • [0059]
    Patients with malignant tumors were subject to a treatment regimen involving carboplatin and 1,25D3, but 48 hours prior to treatment, each patient was placed on a low calcium diet (250-300 mg/48 hr) and maintained on that diet for at least 7 days. The treatment schedule for the patients is as indicated in Table 2.
    TABLE 2
    Cycle Dosage 1,25D3 Dosage carboplatin
    1  4 μg, SQ, QD 1-3 AUC 5 × 1
    2  6 μg, SQ, QD 1-3 AUC 5 × 1
    3  8 μg, SQ, QD 1-3 AUC 5 × 1
    4 11 μg, SQ, QD 1-3 AUC 5 × 1
    5 14 μg, SQ, QD 1-3 AUC 5 × 1
    6 18 μg, SQ, QD 1-3 AUC 5 × 1
    7 23 μg, SQ, QD 1-3 AUC 5 × 1
    8 30 μg, SQ, QD 1-3 AUC 5 × 1
    9 39 μg, SQ, QD 1-3 AUC 5 × 1
  • [0060]
    According to this regimen, each cycle lasts four weeks. For successive cycles, the dosage of 1,25D3 is increased by 30%. For the first two cycles, the patients were divided into two groups as follows:
  • [0061]
    Group 1. One day 1, this group of patients was given carboplatin (intravenously as a 30minute infusion in 100 ml of carrier) at a dose calculated to achieve AUC=5. 24 hours later, a plasma sample was taken to determine carboplatin AUC, and the patients were placed on a three-day regimen of subcutaneous 1,25D3 per the schedule indicated in Table 2.
  • [0062]
    Group 2. On day 1, this group of patients was placed on a three-day regimen of subcutaneous 1,25D3. On day 3, the patients were given carboplatin at a dose calculated to achieve AUC=5. 24 hours later, a plasma sample was taken to determine carboplatin AUC.
  • [0063]
    Following the first cycle, the groups switched between pretreatment and post treatment. For the third and subsequent cycles in this treatment, the patients were placed on a three-day regimen of subcutaneous 1,25D3. On day 3, the patients were given carboplatin at a dose calculated to achieve AUC=5. 24 hours later, a plasma sample was taken to determine carboplatin AUC.
  • [0064]
    Following the first two cycles, patients were assessed to determine the effect on carboplatin AUC by pretreatment vs. post treatment with 1,25D3. The AUC of carboplatin was higher in each patient when pretreated with 1,25D3 than when carboplatin was given first (mean AUC=7.8 μg/ml·hr±1.3, carboplatin D1; 6.7 μg/ml·hr±1.3, carboplatin D3). Consistent with the change in AUC, myleosuppression was consistently less in each patient when carboplatin was followed by adjunctive 1,25D3.
  • EXAMPLE 14
  • [0065]
    This example demonstrates a method of treating prostate cancer within a patient by adjunctively administrating a vitamin D derivative and dexamethasone to the patient.
  • [0066]
    Thirty-two patients with androgen-independent prostate cancer were selected on the basis of cancer progression despite anti-androgen withdrawal therapy. The serum prostate-specific antigen (PSA) concentration of each was measured, and they were treated with 1,25D3 and dexamethasone on a regimen indicated in Table 3.
    TABLE 3
    Cycle Dosage 1,25D3 Dosage dexamethasone
    1 (28 days)  8 μg M-W-F each week 4 mg Sun (first week)
    4 mg M-W-F each week
    2 (28 days) 10 μg M-W-F each week 4 mg M-W-F each week
    3 (28 days) 12 μg M-W-F each week 4 mg M-W-F each week
  • [0067]
    Patients were evaluated if they completed this regimen, and of the initial 36 patients, 24 were evaluated based on the change in serum PSA levels. Five of the patients exhibited at least a 50% reduction in PSA levels after this treatment, while in the remaining 19 the rate of disease progression was markedly attenuated. No toxicity was observed in any of these patients. These results indicate that co-administration of a vitamin D (or a derivative) and dexamethasone can successfully treat prostate cancer.
  • EXAMPLE 15
  • [0068]
    This example demonstrates that adjunctive administration of zoledronate significantly decreases hypercalcemia mediated by vitamin D-derivatives.
  • [0069]
    Normal C3H/HeJ mice were pretreated with 10 μg/kg body weight zoledronate and then treated with 0.25 μg 1,25D3 once a day for three days. Control animals received 1,25D3 alone, and one group of animals received only zoledronate. Following the last 1,25D3 treatment, blood was collected at 0, 24 and 48 hours from each mouse, and the serum calcium levels were measures.
  • [0070]
    Initial calcium levels were significantly reduced in experimental animals as compared to control animals (p=0.00002). 24 and 48 hours later, the serum calcium levels in the control animals remained high (17.2±1.1 mg/dl and 16.5±1.1 mg/dl, respectively), while the serum calcium levels in the experimental animals remained reduced (14.7±0.9 mg/dl and 13.4±0.9 mg/dl respectively). Additionally, experimental animals, as well as those treated with zoledronate alone, exhibited less dehydration, piloerection, and cachexia attributable to hypercalcemia than did control animals. These results demonstrate that zoledronate significantly decreases hypercalcemia mediated by vitamin D (or a derivative).
  • EXAMPLE 16
  • [0071]
    This is an example of a clinical dosing schedule for treatment with paclitaxel and 1,25D3 in accordance with the inventive method.
  • [0072]
    Patients with malignant tumors were subject to a treatment regimen involving paclitaxel and 1,25D3. Paclitaxel was supplied as a sterile solution concentrate (6 mg/ml) in polyethoxylated castor oil 50% and dehydrated ethanol USP 50%. Immediately prior to use, this concentrate was diluted to achieve the appropriate dose in volumes of either 0.9% NaCl injection, USP or 5% dextrose injection, USP (DW5). Preparation was performed in glass to avoid leaching of diethylhexylphthalate plasticizer. 1,25D3 was supplied as 0.5 μg tablets from Hoffman-LaRoche Pharmaceutical Corporatoin. The treatment schedule for the patients was as indicated in Table 4.
    TABLE 4
    Cycle Dosage 1,25D3 Dosage paclitaxel
    1  4 μg orally 80 mg/m2 IV
    2  6 μg orally 80 mg/m2 IV
    3  8 μg orally 80 mg/m2 IV
    4 10 μg orally 80 mg/m2 IV
    5 13 μg orally 80 mg/m2 IV
  • [0073]
    According to this regimen, each cycle lasted eight weeks. For successive cycles, the dosage of 1,25D3 was increased by 30%. Within each cycle, 1,25D3 was administered once a day (between 8 am and 12 am) for the first three days. On the third day, 20 mg dexamethasone, 50 mg diphenhydramine, 50 mg rantidine, and antiemetic-ondasteron (10 mg) or ganisteron (1 mg) was administered intravenously 90 minutes following the 1,25D3 administration. Two hours following 1,25D3 administration, the paclitaxel was administered intravenously in 250 ml neutral saline over one hour. Following four days of rest (days 4-7), the three-day treatment, four-day rest routine was repeated until the last day of paclitaxel administration (day 45). The patients then rested for the remainder of the cycle (days 46-63), following which the next cycle was begun.
  • [0074]
    All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
  • [0075]
    The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
  • [0076]
    Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3741996 *Dec 2, 1971Jun 26, 1973Wisconsin Alumni Res Found1{60 -hydroxycholecalciferol
US4195027 *Jun 12, 1978Mar 25, 1980Wisconsin Alumni Research FoundationProcess for preparing 1α-hydroxylated compounds
US4202829 *Dec 13, 1978May 13, 1980Wisconsin Alumni Research FoundationProcess for preparing 1α-hydroxylated compounds
US4260549 *May 21, 1979Apr 7, 1981Wisconsin Alumni Research FoundationProcess for preparing 1α-hydroxylated compounds
US4508651 *Mar 21, 1983Apr 2, 1985Hoffmann-La Roche Inc.Synthesis of 1α,25-dihydroxyergocalciferol
US4588716 *Jan 16, 1985May 13, 1986Wisconsin Alumni Research FoundationMethod for treating metabolic bone disease in mammals
US4661294 *Mar 18, 1985Apr 28, 1987The General Hospital CorporationBiologically active 1-thio derivatives of vitamin D
US4670190 *Oct 3, 1984Jun 2, 1987Hesse Robert H1-α-hydroxy vitamin D compounds and process for preparing same
US4717721 *May 30, 1985Jan 5, 1988Howard W. BremerSidechain homo-vitamin D compounds with preferential anti-cancer activity
US4728643 *Nov 2, 1984Mar 1, 1988The General Hospital CorporationMethod of treating psoriasis
US4804502 *Jan 20, 1988Feb 14, 1989Hoffmann-La Roche Inc.Vitamin D compounds
US4833125 *May 21, 1987May 23, 1989The General Hospital CorporationMethod of increasing bone mass
US4902481 *Dec 11, 1987Feb 20, 1990Millipore CorporationMulti-well filtration test apparatus
US5087619 *Mar 23, 1990Feb 11, 1992Hoffman-La Roche Inc.Vitamin D3 analogs
US5098899 *Dec 14, 1990Mar 24, 1992Trustees Of Boston UniversityMethod for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5104864 *Aug 17, 1990Apr 14, 1992Bone Care International, Inc.Method for treating and preventing loss of bone mass
US5120722 *Mar 19, 1990Jun 9, 1992Hoffmann-La Roche Inc.Trihydroxy-cholecacliferol and trihydroxy-ergocalciferol for treating leukemia
US5194248 *Jun 21, 1990Mar 16, 1993Trustees Of Boston UniversityCompositions comprising vitamin D analog precursors and the use thereof
US5205989 *Sep 18, 1991Apr 27, 1993Minnesota Mining And Manufacturing CompanyMulti-well filtration apparatus
US5219528 *Aug 6, 1991Jun 15, 1993Pierce Chemical CompanyApparatus for rapid immunoassays
US5292728 *Dec 4, 1992Mar 8, 1994Schering Aktiengesellschaft24-Oxa derivatives in the vitamin D series
US5321016 *Sep 18, 1992Jun 14, 1994Sandoz Pharmaceuticals Corp.Use of certain substituted α-amino acids in treating stress-related psychiatric disorders
US5321018 *Nov 20, 1992Jun 14, 1994Wisconsin Alumni Research FoundationUse of 1α-hydroxylated-19-nor-vitamin D compounds to treat psoriasis
US5403831 *Sep 10, 1993Apr 4, 1995Bone Care International, Inc.Method of treating and preventing loss of bone mass using 1α-hydroxy-vitamin D2
US5411949 *Jan 20, 1992May 2, 1995Schering Aktiengesellschaft23-oxa-derivatives in the vitamin D series, process for their production, pharmaceutical preparations containing these derivatives as well as their use pharmaceutical agents
US5417923 *Jan 18, 1994May 23, 1995Pfizer Inc.Assay tray assembly
US5486509 *May 27, 1994Jan 23, 1996University Of MiamiMethod of preventing and treating chemotherapy-induced alopecia
US5486636 *Oct 26, 1994Jan 23, 1996Wisconsin Alumni Research FoundationSynthesis of 19-nor vitamin D compounds
US5488120 *Aug 24, 1994Jan 30, 1996Lunar Corporation1α-hydroxy vitamin D4 and novel intermediates and analogues
US5512554 *Apr 11, 1995Apr 30, 1996Hoffmann-La Roche Inc.Method of treating hyperproliferative skin diseases with fluorinated vitamin D3 analogs
US5527524 *Apr 5, 1993Jun 18, 1996The Dow Chemical CompanyDense star polymer conjugates
US5529991 *Feb 22, 1994Jun 25, 1996Lunar CorporationOral 1α-hydroxyprevitamin D
US5597575 *Jun 6, 1994Jan 28, 1997Breitbarth; RichardComposition for stimulating and inducing hair growth
US5602116 *Apr 3, 1995Feb 11, 1997Bone Care International, Inc.Method for treating and preventing secondary hyperparathyroidism
US5612327 *Sep 1, 1994Mar 18, 1997Teijin Limited1α,24-(OH)2 -cholecalciferol emulsion composition and method for treating psoriasis
US5614513 *Jun 7, 1995Mar 25, 1997Bone Care International, Inc.Oral 1α-hydroxyprevitamin D
US5616571 *Jun 6, 1995Apr 1, 1997Merck & Co., Inc.Bisphosphonates prevent bone loss associated with immunosuppressive therapy
US5637742 *Nov 1, 1994Jun 10, 1997Duphar International Research B.V.Vitamin D compound, method of preparing this compound and intermediate therefor
US5739271 *Jun 7, 1995Apr 14, 1998Gen-Probe IncorporatedThiocationic lipids
US5753638 *Jun 2, 1995May 19, 1998Hoffmann-La Roche Inc.Method of treating hyperproliferative skin disease with Vitamin D3 fluorinated analogs
US5763428 *Jun 7, 1995Jun 9, 1998Bone Care International, Inc.Methods of treating skin disorders with novel 1a-hydroxy vitamin D4 compounds and derivatives thereof
US5763429 *Dec 30, 1996Jun 9, 1998Bone Care International, Inc.Method of treating prostatic diseases using active vitamin D analogues
US5902806 *Feb 24, 1997May 11, 1999Sumitomo Pharmaceuticals Company, LimitedCrystalline vitamin D derivative
US5902906 *May 1, 1997May 11, 1999Albemarle CorporationAlkanethiolation process
US5905074 *Dec 18, 1997May 18, 1999Hoffmann-La Roche Inc.Vitamin D derivative
US6015801 *Aug 14, 1998Jan 18, 2000Merck & Co., Inc.Method for inhibiting bone resorption
US6025346 *Jun 24, 1994Feb 15, 2000Bone Care International, Inc.1α-hydroxy vitamin D4 and novel intermediates and analogues
US6028064 *Sep 13, 1996Feb 22, 2000New Life Pharmaceuticals Inc.Prevention of ovarian cancer by administration of progestin products
US6034074 *Jun 11, 1997Mar 7, 2000New Life Pharmaceuticals Inc.Prevention of ovarian cancer by administration of a Vitamin D compound
US6040300 *Apr 7, 1995Mar 21, 2000Arch Development CorporationMethod of preventing colon cancer with vitamin D3 analogues
US6051567 *Aug 2, 1999Apr 18, 2000Abbott LaboratoriesLow oxygen content compositions of 1α, 25-dihydroxycholecalciferol
US6071897 *Jul 15, 1998Jun 6, 2000Wisconsin Alumni Research FoundationUse of vitamin D compounds to prevent transplant rejection
US6187764 *Feb 1, 1999Feb 13, 2001Angelina Pinal ButtzA and D vitamins and their metabolites: A new treatment for seasonal allergic rhinitis and atopy
US6211168 *Jun 7, 1995Apr 3, 2001Bone Care International, IncMethods for preparation and use of 1α,24 (S)-dihydroxy vitamin D2
US6218430 *Aug 24, 1998Apr 17, 2001Ligand Pharmaceuticals IncorporatedVitamin D3 mimics
US6221911 *Jun 7, 1996Apr 24, 2001Karo Bio AbUses for thyroid hormone compounds or thyroid hormone-like compounds
US6242434 *May 29, 1998Jun 5, 2001Bone Care International, Inc.24-hydroxyvitamin D, analogs and uses thereof
US6349457 *Mar 19, 2001Feb 26, 2002Emtec Magnetics GmbhProcess and apparatus for disassembling tape cassettes
US6358939 *Dec 21, 1999Mar 19, 2002Northern Lights Pharmaceuticals, LlcUse of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
US6359152 *May 15, 2001Mar 19, 2002Wisconsin Alumni Research Foundation18-substituted-19-nor-vitamin D compounds
US6369088 *Mar 6, 2001Apr 9, 2002Aventis Pharma Deutschland GmbhSubstituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals
US6369098 *Oct 4, 2000Apr 9, 2002Bethesda Pharmaceuticals, Inc.Dithiolane derivatives
US6369099 *Apr 20, 2000Apr 9, 2002Wisconsin Alumni Research FoundationMethod of locking 1 α-OH of vitamin D compounds in axial orientation
US6395784 *May 31, 2001May 28, 2002Bristol-Myers Squibb CompanyBenzamide ligands for the thyroid receptor
US6503893 *Jun 26, 2001Jan 7, 2003Bone Care International, Inc.Method of treating hyperproliferative diseases using active vitamin D analogues
US6506912 *Oct 31, 2001Jan 14, 2003Wisconsin Alumni Research FoundationMethod of locking 1α-OH of vitamin D compounds in axial orientation
US6521222 *Sep 28, 2000Feb 18, 2003Societe L'oreal S.A.Inorganic/organic complexes for reducing skin irritation
US6521608 *Mar 25, 1999Feb 18, 2003Oregon Health & Science UniversityVitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
US6524594 *May 26, 2000Feb 25, 2003Johnson & Johnson Consumer Companies, Inc.Foaming oil gel compositions
US6531460 *Oct 22, 1999Mar 11, 2003Teijin LimitedVitamin D, derivatives and remedies for inflammatory respiratory diseases containing the same
US6537982 *Feb 23, 1998Mar 25, 2003Bone Care International, Inc.Method of treating prostatic diseases using active vitamin D analogues
US6538037 *Jun 26, 2001Mar 25, 2003Bone Care International, Inc.Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2
US6541670 *Nov 29, 2000Apr 1, 2003Leo Pharmaceutical Products Ltd. A/SAminobenzophenones as inhibitors of IL 1β and TNF-α
US6548489 *Jan 4, 2002Apr 15, 2003Teijin LimitedVitamin D3 derivative and treating agent for inflammatory respiratory disease using same
US6552009 *Jun 1, 2001Apr 22, 2003Gentrix LlcCompositions and methods of treating abnormal cell proliferation
US6555710 *Jul 11, 2000Apr 29, 2003Leo Pharmaceutical Products Ltd A/S Lovens Kemiske Fabrik ProduktionsaktieselskabAminobenzophenones as inhibitors of IL-1 β and TNF-α
US6559139 *Apr 6, 2000May 6, 2003University Of Pittsburgh Of The Commonwealth System Of Higher EducationCombination chemotherapy
US6566351 *Dec 27, 1996May 20, 2003Chugai Seiyaku Kabushiki KaishaMalignant tumor metastasis inhibitors
US6566353 *Jun 26, 2001May 20, 2003Bone Care International, Inc.Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US6680309 *Jan 7, 2003Jan 20, 2004Bone Care International, Inc.Method of treating hyperproliferative diseases using active vitamin D analogues
US6689766 *Jan 4, 2002Feb 10, 2004Teijin LimitedVitamin D3 derivative and treating agent for inflammatory respiratory disease using same
US6703380 *Apr 5, 2001Mar 9, 2004Colotech A/SPrevention of cancer
US6867313 *Jan 4, 2002Mar 15, 2005Teijin LimitedVitamin D3 derivative and treating agent for inflammatory respiratory disease using same
US6869940 *May 1, 2002Mar 22, 2005Chugai Seiyaku Kabushiki KaishaMalignant tumor metastasis inhibitors
US6890914 *Sep 11, 2002May 10, 2005Wisconsin Alumni Research FoundationMethod of locking 1α-OH of vitamin D compounds in axial orientation
US6982258 *Oct 15, 2002Jan 3, 2006Cytochroma Inc.Low-calcemic oxime analogs of 1α,25-dihydroxy vitamin D3
US6989377 *Jun 13, 2002Jan 24, 2006Wisconsin Alumni Research FoundationTreating vitamin D responsive diseases
US20010002396 *Jul 16, 1998May 31, 2001Charles AchkarCompositions and methods of treating skin conditions
US20020006917 *Jul 20, 2001Jan 17, 2002Wisconsin Alumni Research FoundationMethod of locking 1alpha-OH of vitamin D compounds in axial orientation
US20020010165 *Jun 26, 2001Jan 24, 2002Bone Care International, Inc.Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US20020019375 *Jun 26, 2001Feb 14, 2002Bone Care International, Inc.Method of inhibiting angiogenesis using active vitamin D analogues
US20020025950 *Jun 26, 2001Feb 28, 2002Bone Care International, Inc.Method of treating hyperproliferative diseases using active vitamin D analogues
US20020035097 *Sep 17, 2001Mar 21, 2002Jimenez Joaquin J.Method of preventing and treating chemotherapy-induced alopecia
US20020049344 *Apr 21, 1997Apr 25, 2002Andreas SteinmeyerNew vitamin d derivatives with carbo-or heterocyclic substituents at c-25, a process for their production, intermediate products and their use for producing medicaments
US20030040508 *Sep 11, 2002Feb 27, 2003Wisconsin Alumni Research FoundationMethod of locking 1alpha-OH of vitatmin D compounds in axial orientation
US20030045509 *Aug 20, 2002Mar 6, 2003Bone Care International, Inc.Stabilized hydroxyvitamin D
US20030096875 *Jul 15, 2002May 22, 2003Graham BurtonOxidized carotenoid fractions and ketoaldehyde useful as cell-differentiation inducers, cytostatic agents, and anti-tumor agents
US20040019023 *Jun 14, 2001Jan 29, 2004Kazumi MorikawaVitamin d derivatives
US20040023934 *Mar 25, 2003Feb 5, 2004Bone Care International, Inc.Method of treating prostatic diseases using active vitamin D analogues
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US20050101576 *May 10, 2004May 12, 2005Novacea, Inc.Methods of using vitamin D compounds in the treatment of myelodysplastic syndromes
US20060148752 *Feb 28, 2006Jul 6, 2006Johnson Candace SMethod of treating soild tumors and leukemias using combination therapy of vitamin D and anti-metabolic nucleoside analogs
US20060177374 *Dec 12, 2005Aug 10, 2006Novacea, Inc.Treatment of cancer with active vitamin D compounds in combination with radiotherapeutic agents and treatments
US20060178351 *Dec 12, 2005Aug 10, 2006Novacea, Inc.Treatment of immune-mediated disorders with active vitamin D compounds alone or in combination with other therapeutic agents
US20070027120 *Sep 7, 2006Feb 1, 2007Whitehouse Martha JMethods of using vitamin D compounds in the treatment of myelodysplastic syndromes
US20070275934 *May 10, 2005Nov 29, 2007Curd John GTreatment of pancreatic cancer with active vitamin d compounds in combination with other treatments
Classifications
U.S. Classification514/168, 514/102, 514/492, 424/649, 514/89, 514/170, 514/34
International ClassificationA61K31/593, A61K31/282, A61K31/337, A61K45/00, A61P43/00, A61P35/00, A61K45/06, A61K33/24, A61K31/59, A61K31/675
Cooperative ClassificationA61K31/573, A61K33/24, A61K31/675, A61K45/06, A61K31/337, A61K31/59
European ClassificationA61K33/24, A61K31/59, A61K31/675, A61K31/573, A61K31/337, A61K45/06
Legal Events
DateCodeEventDescription
Aug 1, 2008ASAssignment
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF
Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF PITTSBURGH;REEL/FRAME:021326/0676
Effective date: 20030903
Jan 22, 2016ASAssignment
Owner name: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR, MA
Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF PITTSBURGH;REEL/FRAME:037576/0269
Effective date: 20160115