Methods and pharmaceutical compositions for inhibiting tumor cell growth

• US 6,242,196 B1
• Filed: 09/17/1999
• Issued: 06/05/2001
• Est. Priority Date: 12/11/1997
• Status: Expired due to Term

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Altiok, Soner, Spiegelman, Bruce M., Mueller, Elisabetta, Tontonoz, Peter, Sarraf, Pasha
• Primary Examiner(s): Leary, Louise N.
• Application Number:
  US09/319,769
• Time in Patent Office: 627 Days
• Field of Search: 435/7.1, 435/4, 435/18, 548/146
• US Class Current: 435/7.1
• CPC Class Codes: A61K 31/426 1,3-Thiazoles

Abstract

A method for inhibiting proliferation of a PPAR γ-responsive hyperproliferative cell which comprises the step of contacting the cell with (I) an inhibitory amount of a PPARγ agonist and (II) a MAP kinase inhibitor is disclosed. A method for treating or prophylactically preventing in an animal subject a disorder characterized by unwanted proliferation of PPARγ-responsive hyperproliferative cells which comprises administering to the subject (I) an inhibitory amount of a PPARγ agonist and (II) a MAP kinase inhibitor is also disclosed. Pharmaceutical compositions comprising a therapeutically effective amount of a PPARγ agonist and a MAP kinase inhibitor are disclosed for use in the methods.

Claims

1. A method for inhibiting proliferation of a PPARγ

-responsive hyperproliferative cell, comprising contacting the cell with a) a PPARγ

agonist in an amount effective to inhbit proliferation of the cell, and b) a MAP kinase inhibitor.

3. The method of claim 1, wherein the PPARγ

agonist is a ligand of a PPARγ

protein, which ligand activates a transcriptional activity of the PPARγ

protein.

4. The method of claim 1, wherein the PPARγ

agonist is a thiazolidinedione, or an analog thereof.

5. The method of claim 1, wherein the PPARγ

agonist is represented in the general formula;

or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

in which A₁ represents a substituted or unsubstituted aromatic heterocyclyl group;

R₁ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;

R₂ and R₃ each represent hydrogen, or R₂ and R₃ together represent a bond;

A₂ represents a benzyl or chromanyl moiety having, as valence and stability permit, up to five substituents; and

n represents an integer in the range of from 1 to 6.

6. The method of claim 5, wherein the PPARγ

agonist is a compound selected from the group consisting of pioglitazone, troglitazone, ciglitazone, englitazone, and BRL49653.

7. The method of claim 1, wherein the PPARγ

agonist is an arachidonate metabolite.

8. The method of claim 1, wherein the PPARγ

agonist is a metabolite of PGD₂.

9. The method of claim 1, wherein the PPARγ

agonist activates PPARγ

-dependent transcription at a concentration at least one order of magnitude less than that required for the same level of activation of PPARα

, PPARδ

or RaR-dependent transcription.

10. The method of claim 1, further comprising contacting the cell with, or administering to the subject animal, an agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, and agents which increase immune responses to tumors.

11. The method of claim 1, wherein the MAP kinase inhibitor is PD098059.

12. The method of claim 1, wherein the cell is derived from an adipose cell or an adipose precursor cell.

13. The method of claim 12, wherein the cell is a liposarcoma cell.

14. The method of claim 1, wherein the cell is derived from an hemopoietic cell or an hemopoietic precursor cell.

15. The method of claim 14, wherein the cell is derived from malignant transformation of a cell of the lymphoid or myeloid lineage.

34. The method of claim 1, wherein inhibiting proliferation of the cell induces differentiation of the cell to a phenotype of lower proliferative index.

2. A method of treating or prophylactically preventing, in a subject animal, a disorder characterized by unwanted proliferation of PPARγ

-responsive hyperproliferative cells, comprising administering to the animal a pharmaceutical preparation of a) a PPARγ

agonist in an amount effective to inhibit growth of the PPARγ

-responsive hyperproliferative cells, and b) a MAP kinase inhibitor.

16. The method of claim 2, wherein the disorder comprises an adipose cell tumor.

17. The method of claim 16, wherein the adipose cell tumor disorder is selected from the group consisting of lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibernomas, hemangiomas and liposarcomas.

18. The method of claim 16, wherein the adipose cell tumor disorder is a liposarcoma.

19. The method of claim 2, wherein the disorder is selected from the group consisting of sarcoma, carcinoma and leukemia.

20. The method of claim 19, wherein the disorder is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblascoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

21. The method of claim 19, wherein the disorder comprises a carcinoma forming from tissue of the breast, prostate, kidney, bladder or colon.

22. The method of claim 19, wherein the disorder comprises a leukemic cancer.

23. The method of claim 2, wherein the subject animal is a mammal.

24. The method of claim 23, wherein the subject animal is a human.

35. The method of claim 2, wherein the MAP kinase inhibitor is PD098059.

25. A pharmaceutical composition comprising:

(i) a PRARγ

agonist in a therpaeutically effective amount to induce terminal differentiation of a PPARγ

-responsive hyperproliferative cell in a subject animal;

(ii) at least one agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, and agents which increase immune responses to tumors;

(iii) a MAP kinase inhibitor; and

[(iii)] (iv) a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 25, wherein the PPARγ

agonist is a thiazolidinedione, or an analog thereof.

28. The pharmaceutical composition of claim 25, wherein the PPARγ

agonist is represented in the general formula;

or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

in which A₁ represents a substituted or unsubstituted aromatic heterocyclyl group;

R₁ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;

R₂ and R₃ each represent hydrogen, or R₂ and R₃ together represent a bond;

A₂ represents a benzyl or chromanyl moiety having, as valence and stability permit, up to five substituents; and

n represents an integer in the range of from 1 to 6.

29. The pharmaceutical composition of claim 28, wherein the PPARγ

agonist is a compound selected from the group of pioglitazone, troglitazone, ciglitazone, englitazone, and BRL49653.

30. The pharmaceutical composition of claim 25, wherein the PPARγ

agonist is an arachidonate metabolite.

31. The pharmaceutical composition of claim 30, wherein the PPARγ

agonist is a metabolite of PGD₂.

32. The pharmaceutical composition of claim 25, wherein the PPARγ

agonist activates PPARγ

-dependent transcription at a concentration at least one order of magnitude less than required for the same level of activation of PPARα

, PPARδ

or RaR-dependent transcription.

26. A pharmaceutical composition comprising a PPARγ

agonist and a MAP kinase inhibitor in a pharmaceutically acceptable carrier, the PPARγ

agonist being present in a therpeutically effective amount to induce terminal differentiation of a PPARγ

-responsive hyperproliferative cell in a subject animal.

33. The pharmaceutical composition of claim 26, wherein the MAP kinase inhibitor is PD098059.