Title:
METHOD OF DYNAMIC RETARDATION OF CELL CYCLE KINETICS TO POTENTIATE CELL DAMAGE
Document Type and Number:
WIPO Patent Application WO1997001344
Kind Code:
A3
Abstract:
Method for inducing cell damage by administering a restraining agent (RA) to a target cell population at a concentration and under conditions sufficient to retard but not arrest the progress of the target cells through the cell cycle, and administering a targeted cytotoxic insult (TCI) concomitant with or subsequent to the application of the RA. The invention also relates to a microculture indicator system and auxiliary data analysis procedures for identifying, designing and using new agents as restraining agents or targeted cytotoxic insults, and for improving synergistic combinations of existing agents. In embodiments of the invention, the RA can be a ribonucleotide reductase inhibitor, a dihydrofolate reductase inhibitor, a thymidylate synthase inhibitor, a DNA polymerase inhibitor, a protein kinase inhibitor or a topoisomerase inhibitor. In addition, embodiments of the invention include, as TCI, indole carbazoles, such as staurosporine, K252a, KT5926, and KT5720. In a specific embodiment, the RA is thymidine and the TCI is staurosporine.
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Inventors:
GRIMLEY PHILIP M
MEHTA SUNIL
MEHTA SUNIL
Application Number:
PCT/US1996/010921
Publication Date:
March 27, 1997
Filing Date:
June 26, 1996
Export Citation:
Assignee:
JACKSON H M FOUND MILITARY MED (US)
International Classes:
C07D475/08; A61K31/17; A61K31/40; A61K31/505; A61K31/519; A61K31/70; A61K31/7028; A61K31/7042; A61K31/7052; A61K31/7064; A61K33/24; A61K45/00; A61K45/06; A61P35/00; A61P43/00; C07H15/26; C07H19/073; C07H19/09; (IPC1-7): A61K31/70; A61K31/55
Domestic Patent References:
| WO1995000520A1 | 1995-01-05 | |||
| WO1993000909A1 | 1993-01-21 | |||
| WO1994004541A2 | 1994-03-03 | |||
| WO1993009782A1 | 1993-05-27 | |||
| WO1994018990A1 | 1994-09-01 | |||
| WO1991007180A1 | 1991-05-30 | |||
| WO1992019765A1 | 1992-11-12 |
Foreign References:
| EP0359981A1 | 1990-03-28 | |||
| US4448534A | 1984-05-15 |
Other References:
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GRANT, S. ET AL: "Modulation of 1-[beta-D-Arabinofuranosyl]Cytosine-Induced Apoptosis in Human Myeloid Leukemia Cells by Staurosporine and Other Pharmacological Inhibitors of Protein Kinase C", ONCOLOGY RESEARCH, vol. 6, no. 2, 1994, pages 87 - 99, XP002017533
BENZ, C. ET AL: "Tamoxifen and 5-Fluorouracil in Breast Cancer: Cytotoxic Synergism", CANCER RESEARCH, vol. 43, 1983, pages 5298 - 5303, XP002017534
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FRANKFURT,O.S.: "Combination Chemotherapy and DNA Repair Inhibition", ANTICANCER RESEARCH, vol. 12, no. 6A, 1992, pages 1795 - 1796, XP002018044
FROST P. ET AL: "Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells", CANCER RES. (UNITED STATES), vol. 50, no. 15, 1990, pages 4572 - 4577, XP002024373
CHANG T.T. ET AL: "Synergistic effect of 4-hydroperoxycyclophosphamide and etopside on a human promyelocytic leukemia cell line (HL-60) demonstrated by computer analysis", CANCER RES. (UNITED STATES), vol. 45, no. 6, 1985, pages 2434 - 2439, XP002024374
CHOU T.-C. ET AL: "Quantitation of the synergistic interaction of edatrexate and cisplatin in vitro", CANCER CHEMOTHER. PHARMACOL. (GERMANY), vol. 31, no. 4, 1993, XP002024380
GRANT, S. ET AL: "Modulation of 1-[beta-D-Arabinofuranosyl]Cytosine-Induced Apoptosis in Human Myeloid Leukemia Cells by Staurosporine and Other Pharmacological Inhibitors of Protein Kinase C", ONCOLOGY RESEARCH, vol. 6, no. 2, 1994, pages 87 - 99, XP002017533
BENZ, C. ET AL: "Tamoxifen and 5-Fluorouracil in Breast Cancer: Cytotoxic Synergism", CANCER RESEARCH, vol. 43, 1983, pages 5298 - 5303, XP002017534
CAPIZZI, R.L. ET AL: "Combination Chemotherapy - Theory and Practice", SEMINARS IN ONCOLOGY, vol. 4, no. 2, 1977, pages 227 - 253, XP002017535
FRANKFURT,O.S.: "Combination Chemotherapy and DNA Repair Inhibition", ANTICANCER RESEARCH, vol. 12, no. 6A, 1992, pages 1795 - 1796, XP002018044
FROST P. ET AL: "Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells", CANCER RES. (UNITED STATES), vol. 50, no. 15, 1990, pages 4572 - 4577, XP002024373
CHANG T.T. ET AL: "Synergistic effect of 4-hydroperoxycyclophosphamide and etopside on a human promyelocytic leukemia cell line (HL-60) demonstrated by computer analysis", CANCER RES. (UNITED STATES), vol. 45, no. 6, 1985, pages 2434 - 2439, XP002024374
CHOU T.-C. ET AL: "Quantitation of the synergistic interaction of edatrexate and cisplatin in vitro", CANCER CHEMOTHER. PHARMACOL. (GERMANY), vol. 31, no. 4, 1993, XP002024380
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