CA2385266A1 - Novel cell cycle checkpoint genes and proteins encoded thereby - Google Patents

Novel cell cycle checkpoint genes and proteins encoded thereby Download PDF

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Publication number
CA2385266A1
CA2385266A1 CA002385266A CA2385266A CA2385266A1 CA 2385266 A1 CA2385266 A1 CA 2385266A1 CA 002385266 A CA002385266 A CA 002385266A CA 2385266 A CA2385266 A CA 2385266A CA 2385266 A1 CA2385266 A1 CA 2385266A1
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Prior art keywords
nucleic acid
protein
biologically active
mus81
seq
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CA002385266A
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French (fr)
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CA2385266C (en
Inventor
Paul R. Russell
Jorge E. Vialard
Michael N. Boddy
Paul A. Shanahan
Antonia Lopez-Girona
Cecile-Marie D. D. Denis
Clare H. Mcgowan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Scripps Research Institute
Original Assignee
The Scripps Research Institute
Paul R. Russell
Jorge E. Vialard
Michael N. Boddy
Paul A. Shanahan
Antonia Lopez-Girona
Cecile-Marie D. D. Denis
Janssen Pharmaceutica N.V.
Clare H. Mcgowan
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Publication of CA2385266A1 publication Critical patent/CA2385266A1/en
Application granted granted Critical
Publication of CA2385266C publication Critical patent/CA2385266C/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4738—Cell cycle regulated proteins, e.g. cyclin, CDC, INK-CCR
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases RNAses, DNAses

Abstract

The present invention encompasses novel mammalian cell cycle checkpoint genes/DNA repairgenes, cDNA or genomic DNA, isolated nucleic acids corresponding thereto, expression vectors comprising said nucleic acids, host cells transformed with said expression vectors, pharmaceutical compositions and the formulation of such compositions comprising said nucleic acids or proteins expressed therefrom, methods for treating a cell using such nucleic acids, proteins or pharmaceutical compositions, and the use of such nucleic acids or proteins in formulating a pharmaceutical preparation.

Claims (117)

1 An isolated nucleic acid encoding for a mammalian Mus81 protein.
2. A nucleic acid of claim 1 encoding for a human Mus81 protein or a biologically active portion thereof.
3. A nucleic acid of claim 2, wherein said nucleic acid encodes for a human Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:2.
4. A nucleic acid of claim 2, wherein said nucleic acid encodes for a human Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:4.
5. A nucleic acid of claim 2, wherein said nucleic acid encodes for a human Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:8.
6. A nucleic acid of claim 2, wherein said nucleic acid encodes for a human Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:10.
7. A nucleic acid of claim 2 having a nucleotide sequence corresponding to that represented by nucleotides 23-1675 of the nucleotide sequence depicted in SEQ
ID NO.:1.
8. A nucleic acid of claim 2 having a nucleotide sequence corresponding to that represented by nucleotides 185-1549 of the nucleotide sequence depicted in SEQ ID NO.:3.
9. A nucleic acid of claim 2 having a nucleotide sequence corresponding to that represented by nucleotides 26-1297 of the nucleotide sequence depicted in SEQ
ID NO.:7.
10. A nucleic acid of claim 2 having a nucleotide sequence corresponding to that represented by nucleotides 26-1681 of the nucleotide sequence depicted in SEQ
ID NO.:9.
11. An expression vector comprising a nucleic acid of claim 2.
12. A host cell transformed with a vector of claim 11.
13. An expression vector comprising a nucleic acid of claim 3.
14. A host cell transformed with a vector of claim 13.
15. An expression vector comprising a nucleic acid of claim 4.
16. A host cell transformed with a vector of claim 15.
17. An expression vector comprising a nucleic acid of claim 5.
18. A host cell transformed with a vector of claim 17.
19. An expression vector comprising a nucleic acid of Claim 6.
20. A host cell transformed with a vector of claim 19.
21. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 3.
22. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 4.
23. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 5.
24. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 6.
25. A biologically active analog of the antisense molecule of claim 21, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
26. A biologically active analog of the antisense molecule of claim 22, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
27. A biologically active analog of the antisense molecule of claim 23, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
28. A biologically active analog of the antisense molecule of claim 24, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
29. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 21.
30. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 22.
31. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 23.
32. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 24.
33. A pharmaceutical preparation for inhibiting human Mus81 protein expression or function in a cell which comprises an antisense nucleic acid analog capable of entering said cell and binding specifically to a nucleic acid molecule encoding for said human Mus81 protein, said antisense nucleic acid being present in a pharmaceutically acceptable carrier and having a nucleotide sequence complementary to at least a portion of a nucleic acid of claim 2.
34. An isolated mammalian Mus81 protein.
35. An isolated protein of claim 34 which is either a human Mus81 protein or marine Mus81 protein.
36. An isolated human Mus81 protein of claim 35 selected from the group of proteins having the amino acid residue sequence corresponding to that depicted by SEQ ID NO.: 2, SEQ ID NO.: 4, SEQ ID NO.: 8, or SEQ ID NO.:10.
37. A fusion protein comprising a protein of claim 35 or biologically active portion thereof.
38. A protein of claim 37 identifiable as Hmus81-GFP.
39. An antibody which specifically binds to a portion of a protein of Claim 36.
40. An antibody of claim 39 that is a polycolonal antibody.
41. An antibody of claim 39 that is a monoclonal antibody.
42. A method for identifying a compound as an inhibitor or activator of expression of the human Mus81 cell cycle checkpoint/repair pathway protein which method comprises contacting a cell expressing the protein in said pathway with said compound and comparing the level of expression of the human Mus81 human cell cycle checkpoint/repair pathway protein of said cell with that of a cell which has not been contacted with said compound.
43. A compound corresponding to one identified by the method of claim 42.
44. A compound identifiable by the method of claim 42, useful for treating cancer or other proliferative diseases.
45. The use of a compound of claim 43 in the preparation of a medicament for the treatment of cancer or proliferative diseases.
46. A pharmaceutical composition comprising a compound according to claim 43, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
47. A pharmaceutical composition comprising a compound of claim 43 together with a DNA damaging chemotherapeutic agent and a pharmaceutically acceptable carrier, diluent or excipient therefor.
48. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of a candidate substance identifiable by the method of claim 42.
49. The method of treating cancer or proliferative disease in a patient, comprising administering a compound of claim 43, to a patient in need of treatment.
50. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 21.
51. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 22.
52. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 23.
53. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 24.
54. The method of treating cancer or proliferative disease in a patient, comprising administering a pharmaceutical preparation of claim 47, to a patient in need of treatment.
55. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an inhibitor compound that inhibits the activity of the human Mus81 protein.
56. A method of identifying a chemical compound that modulates Mus81 dependent cell cycle pathway, which method comprises administering a chemical compound to be tested to a host cell, detecting the level of human Mus81 protein or subsequent cell cycle protein in said cell, and comparing the detected level to that of a normal untreated cell.
57. A chemical compound corresponding to one identified by the method of claim 56.
58. A method of identifying a chemical compound that modulates Mus81 dependent cell cycle pathway, which method comprises administering a chemical compound to be tested to a host cell, detecting the level of human Mus81 protein encoding nucleic acid or subsequent cell cycle protein encoding nucleic acid in said cell, and comparing the detected level to that of a normal untreated cell.
59. A chemical compound corresponding to one identified by the method of claim 58.
60. A method of identifying a chemical compound that modulates Mus81 dependent cell cycle pathway, which method comprises administering a chemical compound to be tested to a biochemical mixture of human Mus81 protein and a suitable substrate, detecting the level of human Mus81 protein activity in said mixture, and comparing the detected level to that of a normal untreated biochemical mixture of human Mus 81 protein.
61. A chemical compound corresponding to one identified by the method of claim 60.
62. A nucleic acid of claim 1 encoding for a marine Mus81 protein or biologically active fragment thereof.
63. A nucleic acid of claim 62, wherein said nucleic acid encodes for a murine Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:12.
64. A nucleic acid of claim 62, wherein said nucleic acid encodes for a murine Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:14.
65. A nucleic acid of claim 62, wherein said nucleic acid encodes for a murine Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:16.
66. A nucleic acid of claim 62, wherein said nucleic acid encodes for a murine Mus81 protein having the amino acid sequence depicted by SEQ ID NO.:18.
67. A nucleic acid of claim 62 having a nucleotide sequence corresponding to that represented by nucleotides 42-1694 of the nucleotide sequence depicted in SEQ
ID NO.:11.
68. A nucleic acid of claim 62 having a nucleotide sequence corresponding to that represented by nucleotides 15-1323 of the nucleotide sequence depicted in SEQ
ID NO.:13.
69. A nucleic acid of claim 62 having a nucleotide sequence corresponding to that represented by nucleotides 52-1644 of the nucleotide sequence depicted in SEQ
ID NO.:15.
70. A nucleic acid of claim 62 comprising nucleic acid having a nucleotide sequence corresponding to that represented by nucleotides 52-1614 of the nucleotide sequence depicted in SEQ ID NO.:17.
71. An expression vector comprising a nucleic acid of claim 62.
72. A host cell transformed with a vector of claim 71.
73. An expression vector comprising a nucleic acid of claim 63.
74. A host cell transformed with a vector of claim 73.
75. An expression vector comprising a nucleic acid of claim 64.
76. A host cell transformed with a vector of claim 75.
77. An expression vector comprising a nucleic acid of claim 65.
78. A host cell transformed with a vector of claim 77.
79. An expression vector comprising a nucleic acid of Claim 66.
80. A host cell transformed with a vector of claim 79.
81. A biologically active antisense molecule comprising a nucleic acid that is the complement of least portion of the nucleic acid of claim 63.
82. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 64.
83. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 65.
84. A biologically active antisense molecule comprising a nucleic acid that is the complement of at least a portion of the nucleic acid of claim 66.
85. A biologically active analog of the antisense molecule of claim 81, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
86. A biologically active analog of the antisense molecule of claim 82, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
87. A biologically active analog of the antisense molecule of claim 83, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
88. A biologically active analog of the antisense molecule of claim 84, said analog being selected from the group consisting of peptide nucleic acids, methylphosphonates and 2-O-methyl ribonucleic acids.
89. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 81.
90. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 82.
91. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 83.
92. A biologically active phosphorothioate analog of the antisense oligonucleotide of claim 84.
93. A pharmaceutical preparation for inhibiting Mus81 protein expression or function in a mammalian cell which comprises an antisense nucleic acid analog capable of entering said cell and binding specifically to a nucleic acid molecule encoding for said Mus81 protein, said antisense nucleic acid being present in a pharmaceutically acceptable carrier and having a nucleotide sequence complementary to at least a portion of the nucleic acid of claim 62.
94. An isolated marine Mus81 protein of claim 35 selected from the group of proteins having the amino acid residue sequences depicted by SEQ ID NO.:
12, SEQ ID NO.: 14, SEQ ID NO.: 16, or SEQ ID NO.:18.
95. An antibody which specifically binds to a portion of a protein of Claim 94.
96. The antibody of claim 95 that is a polycolonal antibody.
97. The antibody of claim 95 that is a monoclonal antibody.
98. A method for identifying a compound as an inhibitor or activator of expression of mammalian Mus81 cell cycle checkpoint/repair pathway protein which method comprises, contacting a cell expressing the protein in said pathway with said compound, detecting the level of expression of the mammalian Mus81 cell cycle checkpoint/repair pathway protein in said cell, and comparing the detected level with that of a cell which has not been contacted with said compound.
99. A compound corresponding to a compound identified by the method of claim 98.
100. A compound identifiable by the method of claim 98, useful for treating cancer or other proliferative diseases.
101. The use of a compound of claim 99 in the preparation of a medicament for the treatment of cancer or proliferative diseases.
102. A pharmaceutical composition comprising a compound according to claim 99, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
103. A pharmaceutical composition comprising a compound of claim 99 together with a DNA damaging chemotherapeutic agent and a pharmaceutically acceptable carrier, diluent or excipient therefor.
104. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of a candidate substance identifiable by the method of claim 98.
105. The method of treating cancer or proliferative disease in a patient, comprising administering a compound of claim 99, to a patient in need of treatment.
106. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 81.
107. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 82.
108. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 83.
109. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an antisense nucleic acid of claim 84.
110. The method of treating cancer or proliferative disease in a patient, comprising administering a pharmaceutical composition of claim 100, to a patient in need of treatment.
111. A method of increasing susceptibility of cancer cells to chemotherapy or radiotherapy, which method comprises administering to a patient a therapeutically effective amount of an inhibitor compound wherein said inhibitor inhibits the activity of the Mmus81 protein.
112. A method of identifying a chemical compound that modulates the Mus81 dependent cell cycle pathway, which method comprises administering a chemical compound to be tested to a host cell, detecting the level of marine Mus81 protein or subsequent cell cycle protein in said cell, and comparing said detected level with that of a normal untreated cell.
113. A chemical compound corresponding to one identifiable by the method of claim 112.
114. A method of identifying a chemical compound that modulates the Mus81 dependent cell cycle pathway, which method comprises administering a chemical compound to be tested to a host cell, detecting the level of murine Mus81 protein encoding nucleic acid or subsequent cell cycle protein encoding nucleic acid in said cell, and comparing said detected level with that of a normal untreated cell.
115. A chemical compound corresponding to one identifiable by the method of claim 114.
116. A method of identifying a chemical compound that modulates the Mus81 dependent cell cycle checkpoint pathway, which method comprises administering the chemical compound to be tested to a biochemical mixture of murine Mus81 protein and a suitable substrate, and detecting if the level of murine Mus81 protein activity in said mixture is altered from that of a normal untreated biochemical mixture of murine Mus81 protein.
117. A chemical compound identifiable by the method of claim 112.
CA2385266A 1999-09-14 2000-09-14 Novel cell cycle checkpoint genes and proteins encoded thereby Expired - Fee Related CA2385266C (en)

Applications Claiming Priority (3)

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US15383699P 1999-09-14 1999-09-14
US60/153,836 1999-09-14
PCT/US2000/025278 WO2001020038A1 (en) 1999-09-14 2000-09-14 Novel cell cycle checkpoint genes and proteins encoded thereby

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EP (1) EP1214453B1 (en)
JP (1) JP4871468B2 (en)
KR (2) KR100817010B1 (en)
AT (1) ATE404693T1 (en)
AU (1) AU784443B2 (en)
CA (1) CA2385266C (en)
DE (1) DE60039895D1 (en)
DK (1) DK1214453T3 (en)
ES (1) ES2311472T3 (en)
IL (2) IL148595A0 (en)
NO (1) NO20021255L (en)
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US20070021361A1 (en) * 2002-12-04 2007-01-25 Shuster Samuel J Methods and materials for modulating trpm2
US7396669B2 (en) * 2004-06-30 2008-07-08 The Scripps Research Institute Mammalian endonucleases and methods of use

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US5801154A (en) * 1993-10-18 1998-09-01 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of multidrug resistance-associated protein
US5552390A (en) * 1993-12-09 1996-09-03 The Board Of Regents Of The University Of Nebraska Phosphorothioate inhibitors of metastatic breast cancer
EP0973935A2 (en) * 1997-03-20 2000-01-26 Variagenics, Inc. Target genes for allele-specific drugs
US5977341A (en) * 1998-11-20 1999-11-02 Isis Pharmaceuticals Inc. Antisense modulation of inhibitor-kappa B kinase-beta expression
US7396669B2 (en) * 2004-06-30 2008-07-08 The Scripps Research Institute Mammalian endonucleases and methods of use

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DE60039895D1 (en) 2008-09-25
ZA200202863B (en) 2003-09-23
US6440732B1 (en) 2002-08-27
EP1214453A1 (en) 2002-06-19
KR100817010B1 (en) 2008-03-27
KR20070043872A (en) 2007-04-25
EP1214453A4 (en) 2003-02-19
EP1214453B1 (en) 2008-08-13
AU7581700A (en) 2001-04-17
US7479541B2 (en) 2009-01-20
CA2385266C (en) 2011-05-24
KR100851511B1 (en) 2008-08-11
NO20021255D0 (en) 2002-03-13
US7214790B2 (en) 2007-05-08
JP2003509069A (en) 2003-03-11
ATE404693T1 (en) 2008-08-15
US20070213256A1 (en) 2007-09-13
US20070072794A1 (en) 2007-03-29
JP4871468B2 (en) 2012-02-08
DK1214453T3 (en) 2008-10-13
IL148595A (en) 2008-11-26
IL148595A0 (en) 2002-09-12
KR20020064781A (en) 2002-08-09
WO2001020038A1 (en) 2001-03-22
NO20021255L (en) 2002-05-03
NZ518236A (en) 2004-02-27
AU784443B2 (en) 2006-04-06

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