Use of histone deacetylase inhibitors in combination with radiation for the treatment of cancer

• US 20040018968A1
• Filed: 04/15/2003
• Published: 01/29/2004
• Est. Priority Date: 04/15/2002
• Status: Abandoned Application

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Rifkind, Richard A., Richon, Victoria M., Marks, Paul A., Sgouros, George
• Application Number:
  US10/413,422
• Publication Number:
  US 20040018968A1
• Time in Patent Office: Days
• US Class Current: 514/9
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a method for the treatment of cancer in a patient in need thereof. The method comprises administering to a patient in need thereof a first amount of a histone deacetylase inhibitor in a first treatment procedure, and a second amount or dose of radiation in a second treatment procedure. The first and second treatments together comprise a therapeutically effective amount. The combination of the HDAC inhibitor and radiation therapy is therapeutically synergistic.

Claims

1. A method for treating cancer in a patient in need thereof comprising administering to said patient a first amount of a histone deacetylase inhibitor in a first treatment procedure, and a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.

2. The method according to claim 1, wherein said HDAC inhibitor is a hydroxamic acid derivative, a Short Chain Fatty Acid (SCFA), a cyclic tetrapeptide, a benzamide derivative, or an electrophilic ketone derivative.

3. The method according to claim 2, wherein said HDAC inhibitor is a hydroxamic acid derivative selected from the group consisting of SAHA, Pyroxamide, CBHA, Trichostatin A (TSA), Trichostatin C, Salicylihydroxamic Acid (SBHA), Azelaic Bishydroxamic Acid (ABHA), Azelaic-1-Hydroxamate-9-Anilide (AAHA), 6-(3-Chlorophenylureido) carpoic Hydroxamic Acid (3Cl-UCHA), Oxamflatin, A-161906, Scriptaid, PXD-101, LAQ-824, CHAP, MW2796, and MW2996.

4. The method according to claim 2, wherein said HDAC inhibitor is a Cyclic Tetrapeptide selected from the group consisting of Trapoxin A, FR901228 (FK 228 or Depsipeptide), FR225497, Apicidin, CHAP, HC-Toxin, WF27082, and Chlamydocin.

5. The method according to claim 2, wherein said HDAC inhibitor is a Short Chain Fatty Acid (SCFA) selected from the group consisting of Sodium Butyrate, Isovalerate, Valerate, 4 Phenylbutyrate (4-PBA), Phenylbutyrate (PB), Propionate, Butyramide, Isobutyramide, Phenylacetate, 3-Bromopropionate, Tributyrin, Valproic Acid and Valproate.

6. The method according to claim 2, wherein said HDAC inhibitor is a Benzamide derivative selected from the group consisting of CI-994, MS-27-275 (MS-275) and a 3′

-amino derivative of MS-27-275.

7. The method according to claim 2, wherein said HDAC inhibitor is an electrophilic ketone derivative selected from the group consisting of a trifluoromethyl ketone and an α

-keto amide.

8. The method according to claim 2, wherein said HDAC inhibitor is Depudecin.

9. The method according to claim 1, wherein said HDAC inhibitor is represented by the following structure:

10. The method according to claim 1, wherein said HDAC inhibitor is pyroxamide, represented by the structure:

11. The method according to claim 1, wherein said HDAC inhibitor is represented by the structure:

12. The method according to claim 1, wherein said HDAC inhibitor is represented by the structure:

13. The method according to claim 1, wherein said HDAC inhibitor is represented by the structure:

14. The method according to claim 1, wherein said HDAC inhibitor is represented by the structure:

15. The method according to claim 1, wherein the radiation of the second treatment procedure is external beam radiation.

16. The method according to claim 1, wherein the radiation of the second treatment procedure is a radiopharmaceutical agent.

17. The method of claim 16, wherein the radiopharmaceutical is a radioactive conjugate.

18. The method according to claim 17, wherein said radioactive conjugate is a radiolabeled antibody.

19. The method according to claim 1, wherein the radiation is selected from the group consisting of:

electromagnetic radiation and particulate radiation.

20. The method according to claim 19, wherein the electromagnetic radiation is selected from the group consisting of:

x-rays, gamma rays and any combination thereof.

21. The method of claim 19, wherein the particulate radiation is selected from the group consisting of:

electron beams (beta particles), protons beams, neutron beams, alpha particles and negative pi mesons.

22. The method of claim 21, wherein the particulate radiation is alpha particles.

23. The method according to claim 1, wherein a total of at least about 1 Gy of radiation is administered to the patient.

24. The method according to claim 1, wherein a total of at least about 10 Gy of radiation is administered to the patient.

25. The method according to claim 1, wherein a total of at least about 20 Gy of radiation is administered to the patient.

26. The method according to claim 1, wherein a total of at least about 40 Gy of radiation is administered to the patient.

27. The method according to claim 1, wherein the therapeutic effect of said HDAC inhibitor and said radiation is synergistic.

28. The method according to claim 26, wherein said HDAC inhibitor sensitizes cancer cells in the patient to radiation.

29. The method according to claim 1, wherein radiation sensitizes cancer cells in the patient to said HDAC inhibitor.

30. The method according to claim 1, wherein said UDAC inhibitor and radiation are administered simultaneously.

31. The method according to claim 1, wherein said HDAC inhibitor and said radiation are administered sequentially.

32. The method according to claim 31, wherein said HDAC inhibitor is administered prior to administering said radiation.

33. The method according to claim 31, wherein said HDAC inhibitor is administered after administering said radiation.

34. The method of claim 1, wherein the HDAC inhibitor is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraoccularly, locally, subcutaneously, intraadiposally, intraarticularly, intrathecally.

35. The method of claim 1, wherein the HDAC inhibitor is in a slow release dosage form.

36. The method of claim 16, wherein the radiopharmaceutical agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraoccularly, locally, subcutaneously, intraadiposally, intraarticularly or intrathecally.

37. The method of claim 16, wherein the radiopharmaceutical agent is in a slow release dosage form.

38. A method of determining the sensitivity of a cancer cell to a combination therapy of an HDAC inhibitor and radiation, said method comprising the step of contacting said cancer cell with a first amount of a histone deacetylase inhibitor in a first treatment procedure, and a second amount of radiation in a second treatment procedure, wherein the first and second treatments together comprise a therapeutically effective amount and assessing the sensitivity of the cell to treatment.

39. A method of determining a therapeutically effective amount of a combination of an HDAC inhibitor and radiation for treating a cancer, comprising the step of exposing a cancer cell to a first amount of a histone deacetylase inhibitor in a first treatment procedure, and a second amount or dose of radiation in a second treatment procedure, wherein the first and second treatments together comprise a therapeutically effective amount and assessing the anticancer effects.

40. A pharmaceutical composition comprising a first amount of a histone deacetylase inhibitor and a second amount of radiation wherein the first and second amounts together comprise a therapeutically effective amount.

41. The composition of claim 40, wherein the radiation is a radiopharmaceutical agent.

42. Use of a first amount of an HDAC inhibitor and a second amount of radiation for the manufacture of a medicament for treating cancer.

43. The use of claim 42, wherein the radiation is a radiopharmaceutical agent.