Claims
- 1. A method for screening for a modulating agent which when combined with an antitumor therapeutic agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with an amount of the modulating agent and with an antitumor therapeutic agent known to cause apotosis when used in combination with an appropriate modulating agent in an amount effective to increases apoptosis in tumor cells; (b) determining the degree of apoptosis of tumor cells from step (a); and (c) comparing the degree of apoptosis determined in step (b) with the degree of apoptosis of tumor cells which are treated with only the antitumor therapeutic agent or only the modulating agent, an increase in apoptosis indicating that the modulating agent in combination with an antitumor therapeutic agent is capable of increasing apoptosis in tumor cells.
- 2. A method for screening for a modulating agent which when combined with an antitumor therapeutic agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with an amount of the modulating agent for a period of time; (b) contacting the tumor cells from step (a) with an antitumor therapeutic agent known to increase apotosis when used in combination with a modulating agent in an amount effective to increase apoptosis; (c) determining the degree of apoptosis of tumor cells from step (b); and (d) comparing the degree of apoptosis determined in step (b) with the degree of apoptosis of tumor cells which are treated with only the modulating agent, or only the antitumor therapeutic agent, an increase in apoptosis indicating that the modulating agent in combination with an antitumor therapeutic agent is capable of increasing apoptosis in tumor cells.
- 3. A method for screening for a modulating agent which when combined with an antitumor therapeutic agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with an antitumor therapeutic agent known to increases apoptosis in tumor cells when used in combination with an appropriate modulating agent in an amount effective to increase apoptosis for a period of time; (b) contacting the tumor cells from step (a) with an amount of the modulating agent; (c) determining the degree of apoptosis of tumor cells from step (b); and (d) comparing the degree of apoptosis determined in step (b) with the degree of apoptosis of tumor cells which are treated with only the antitumor therapeutic agent or only the modulating agent, an increase in apoptosis indicating that the modulating agent in combination with an antitumor therapeutic agent is capable of increasing apoptosis in tumor cells.
- 4. A method according to any of claim 1 to 3, wherein the modulating agent is a chemical compound that inhibits cellular apoptotic signalling.
- 5. A method according to claim 4, wherein the modulating agent is a protein kinase C inhibitor.
- 6. A method according to any of claim 1 to 5, wherein the modulating agent is not previously known.
- 7. The modulating agent capable of increasing apoptosis in tumor cells as determined by the method of claim 6.
- 8. A pharmaceutical composition comprising the modulating agent capable of increasing apoptosis in tumor cells as determined by the method any of claim 1 to 7, and a pharmaceutically acceptable carrier.
- 9. A method for screening for an antitumor therapeutic agent which when combined with a modulating agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with a modulating agent known to increase apoptosis in tumor cells when used in combination with an appropriate antitumor therapeutic agent in an amount effective to increases apoptosis in tumor cells and with an amount of the antitumor therapeutic agent; (b) determining the degree of apoptosis of tumor cells from step (a); and (c) determining the degree of apoptosis of tumor cells from step (b); and (d) comparing the degree of apoptosis determined in step (c) with the degree of apoptosis of tumor cells which are treated with only the modulating agent or only the antitumor therapeutic agent, an increase in apoptosis indicating that the antitumor therapeutic agent in combination with the modulating agent is capable of increasing apoptosis in tumor cells.
- 10. A method for screening for an antitumor therapeutic agent which when combined with a modulating agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with a modulating agent known to increase apoptosis in tumor cells when used in combination with an appropriate antitumor therapeutic agent in an amount effective to increases apoptosis in tumor cells for a period of time; (b) contacting the tumor cells from step (a) with an amount of the antitumor therapeutic agent; (c) determining the degree of apoptosis of tumor cells from step (b); and (d) comparing the degree of apoptosis determined in step (c) with the degree of apoptosis of tumor cells which are treated with only the modulating agent or only the antitumor therapeutic agent, an increase in apoptosis indicating that the antitumor therapeutic agent in combination with the modulating agent is capable of increasing apoptosis in tumor cells.
- 11. A method for screening for an antitumor therapeutic agent which when combined with a modulating agent increases apoptosis in tumor cells comprising the steps of:
(a) contacting tumor cells with an amount of the antitumor therapeutic agent for a period time; (b) contacting the tumor cells from step (a) with a modulating agent known to increase apoptosis in tumor cells when used in combination with an appropriate antitumor therapeutic agent in an amount effective to increases apoptosis in tumor cells; (c) determining the degree of apoptosis of tumor cells from step (b); and (d) comparing the degree of apoptosis determined in step (c) with the degree of apoptosis of tumor cells which are treated with only the modulating agent or only the antitumor therapeutic agent, an increase in apoptosis indicating that the antitumor therapeutic agent in combination with the modulating agent is capable of increasing apoptosis in tumor cells.
- 12. A method according to claim 9, 10 or 11, wherein the antitumor therapeutic agent is not previously known.
- 13. The antitumor therapeutic agent suitable for combination therapy with a modulating agent capable of increasing apoptosis in tumor cells by the method of claim 12.
- 14. A pharmaceutical composition comprising an effective amount of at least one antitumor therapeutic agent determined by the method of claim 9, 10 or 11, at least one modulating agent capable of increasing apoptosis in tumor cells, and a pharmaceutically acceptable carrier.
- 15. A method for treating cancer in a subject comprising administering to the subject an effective amount of at least one antitumor therapeutic agent, and at least one modulating agent, sequentially or concomitantly.
- 16. A method according to claim 15, wherein the tumor bearing subject is administered at least one antitumor therapeutic agent and subsequently administered at least one modulating agent.
- 17. A method according to claim 15 or 16, wherein the antitumor therapeutic agent is paclitaxel and the modulating agent is flavopiridol.
- 18. A method according to claim 15 or 16, wherein the antitumor therapeutic agent is mitomycin C and the modulating agent is Ro32-0432.
- 19. A method according to claim 15, wherein the tumor bearing subject is administered at least one modulating agent and subsequently administered at least one antitumor therapeutic agent.
- 20. A method according to claim 15 or 19, wherein the modulating agent is safingol and the antitumor therapeutic agent is mitomycin C or doxorubicin.
- 21. A method according to claim 15, wherein the tumor bearing subject is administered at least one modulating agent concomitantly with at least one antitumor agent.
- 22. A method according to claim 15 or 21, wherein the modulating agent is flavopiridol and the antitumor therapeutic agent is mitomycin C.
- 23. A method according to claim 15 or 21, wherein the modulating agents are safingol and UCN-01, and antitumor therapeutic agent is mitomycin C.
- 24. A method according to claim 15 or 21, wherein the modulating agent is UCN-01 and the antitumor therapeutic agent is mitomycin C.
- 25. A method according to claim 15 or 21, wherein the modulating agent is Ro-1 and the antitumor therapeutic agent is mitomycin C.
- 26. A method according to claim 15 or 21, wherein the modulating agent is safingol and the antitumor therapeutics agents are paclitaxel and mitomycin C.
- 27. A method of claim 15, wherein the modulating agent is selected from the group consisting of Safingol (L-threo-dihydrosphingosine), Ro-1 (Bisindolylmaleimide), Ro32-0432 (Bisindolylmaleimide tertiary amine), UCN-01 (7-OH-staurosporine), Flavopiridol (L86-8275), Bryostatin 1 (macrocyclic lactone), and antisense nucleotides capable of inhibiting the expression of protein kinase C.
- 28. A method of claim 27, wherein the antisense nucleotide capable of inhibiting the expression of protein kinase C is protein kinase C a antisense.
- 29. A method of claims 1, 2, 3, 7, 8, 9, or 15, wherein one or more of the antitumor therapeutic agents is a chemotherapeutic agent.
- 30. A method of claim 29, wherein the chemotherapeutic agent is selected from a group consisting of mitomycin C, carboplatin, cisplatin, paclitaxel, etoposide, and doxorubicin.
- 31. A method of claim 1, 2, 3, 7, 8, 9, or 15, wherein at least one of the antitumor therapeutic agents is a radiotherapeutic agent.
- 32. A method of claim 15, wherein the cancer is a gastrointestinal cancer, breast cancer or an ovarian cancer.
- 33. A method of claim 32, wherein the gastrointestinal cancer is selected from a group consisting of gastric cancer, small bowel cancer, colon cancer, and rectal cancer.
- 34. A method of claim 15, wherein the tumor is selected from a group consisting of lymphoma, adenocarcinoma, glioblastoma, leukemia, esophageal carcinoma, head and neck cancer, prostate cancer, lung cancer, melanoma, cervical carcinoma, pancreatic cancer, sarcoma, hepatoma, and gallbladder cancer.
- 35. A method for increasing apoptosis in tumor cells comprising contacting tumor cells with an effective amount of a modulating agent capable of increasing apoptosis during, prior to, or after treatment with one or more antitumor therapeutic agents.
Parent Case Info
[0001] This application is a continuation-in-part application of U.S. Ser. No. 08/619,304, filed Mar. 21, 1996 which is a continuation-in-part application U.S. Ser. No. 08/603,814, filed Feb. 20, 1996, the contents of which are hereby incorporated by reference into the present application.
[0002] Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of each series of experiments in this application, preceding the claims.
Continuations (2)
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Number |
Date |
Country |
Parent |
09137442 |
Aug 1998 |
US |
Child |
10215178 |
Aug 2002 |
US |
Parent |
PCT/US97/03341 |
Feb 1997 |
US |
Child |
09137442 |
Aug 1998 |
US |
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
08619304 |
Mar 1996 |
US |
Child |
PCT/US97/03341 |
Feb 1997 |
US |
Parent |
08603814 |
Feb 1996 |
US |
Child |
08619304 |
Mar 1996 |
US |