Methylenetetrahydrofolate reductase inhibitors and uses thereof

• US 20040121972A1
• Filed: 11/20/2003
• Published: 06/24/2004
• Est. Priority Date: 12/03/2001
• Status: Active Grant

• Current Assignee: Rima Rozen
• Original Assignee: Rima Rozen
• Inventors: Rozen, Rima, Sekhon, Jaspreet
• Granted Patent: US 7,319,145 B2
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C12Y 105/0102 Methylenetetrahydrofolate reductase [NAD(P)H] (1.5.1.20)

Abstract

The present invention provides methylenetetrahydrofolate reductase (MTHFR) inhibitors for use in selective inhibition of cancer cell growth in a mammal. These inhibitors can be a small molecule, an antisense oligonucleotide, a ribozyme, a triple helix forming oligonucleotide, an anti-MTHFR antibody or fragment thereof, an MTHFR mutant or a fragment of MTHFR. The present invention further provides nucleic acids encoding an inhibitor of MTHFR, and vectors comprising these nucleic acids. Also encompassed by the present invention are methods of using the MTHFR inhibitors for selective inhibition of cancer cell growth, and pharmaceutical compositions comprising the MTHFR inhibitors.

Claims

1. An inhibitor of methylenetetrahydrofolate reductase (MTHFR) for use in selective inhibition of cancer cell growth in a mammal in need of such therapy, wherein the inhibitor reduces MTHFR gene expression or MTHFR activity.

2. The inhibitor according to claim 1, which is a non-allele specific antisense oligonucleotide at least 7 nucleotides in length that comprises a sequence that is complementary to a gene encoding MTHFR.

3. The inhibitor according to claim 2, wherein the oligonucleotide comprises a sequence as set forth in SEQ ID NO:

16.

4. The inhibitor according to claim 1, which is a ribozyme.

5. The inhibitor according to claim 1, which is an antibody or an antibody fragment that binds to and inhibits MTHFR.

6. The inhibitor according to claim 1, which is a small molecule.

7. The inhibitor according to claim 5, which is a peptide.

8. The inhibitor according to claim 1, which is a mutant MTHFR or a fragment of MTHFR.

9. The inhibitor according to any one of claims 1, 2, 3, 4, 5, 6, 7, or 8, wherein said inhibition of cancer cell growth sensitizes the cancer cells to an anti-cancer therapeutic.

10. The inhibitor according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said mammal has cancer.

11. The inhibitor according to claim 10, wherein said cancer is a breast cancer, colon carcinoma, colorectal carcinoma, neuroblastoma, or glioma.

12. The inhibitor according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein said mammal is a human.

13. A nucleic acid comprising a sequence encoding the inhibitor according to any one of claims 2, 3, 4, 5, 7 or 8.

14. The nucleic acid according to claim 13, which is operatively associated with a regulatory control element.

15. The nucleic acid according to claim 14, wherein said regulatory control element is a transcriptional control element.

16. A vector comprising the nucleic acid according to claim 13, 14, or 15.

17. A pharmaceutical composition comprising the inhibitor according to any one of claims 1, 2, 3, 4, 5, 6, 7, or 8, and a pharmaceutically acceptable carrier, diluent or excipient.

29. Use of the vector according to claim 16 for the manufacture of a medicament, wherein the inhibitor selectively inhibits cancer cell growth and wherein the inhibitor reduces methylenetetrahydrofolate reductase (MTHFR) gene expression or MTHFR activity.

30. The use according to claim 29, wherein the inhibitor sensitizes the cancer cells to an anti-cancer therapeutic.

31. The use according to claim 29, wherein the medicament additionally comprises an anti-cancer therapeutic.

32. The use according to any one of claims 29, 30, or 31, wherein the medicament is for treating, stabilizing or preventing cancer in a mammal.

33. The use according to claim 32, wherein wherein said cancer is a breast cancer, colon carcinoma, colorectal carcinoma, neuroblastoma, or glioma.

34. The use according to any one of claims 29, 30, 31, 32, or 33, wherein the mammal is a human.

18. Use of a methylenetetrahydrofolate reductase (MTHFR) inhibitor for the manufacture of a medicament, wherein the inhibitor reduces MTHFR gene expression or MTHFR activity.

19. The use according to claim 18, wherein the inhibitor is a non-allele specific antisense oligonucleotide at least 7 nucleotides in length that comprises a sequence that is complementary to a gene encoding MTHFR.

20. The use according to claim 19, wherein the oligonucleotide comprises SEQ ID NO:

16.

21. The use according to claim 18, wherein the inhibitor is an antibody or an antibody fragment that binds to and inhibits MTHFR.

22. The use according to claim 18, wherein the inhibitor is a small molecule.

23. The use according to claim 18, wherein the inhibitor is a mutant MTHFR or a fragment of MTHFR.

24. The use according to any one of claims 18, 19, 20, 21, 22, or 23, wherein the inhibitor sensitizes the cancer cells to an anti-cancer therapeutic.

25. The use according to any one of claims 18, 19, 20, 21, 22, or 23, wherein the medicament additionally comprises an anti-cancer therapeutic.

26. The use according to any one of claims 18, 19, 20, 21, 22, 23, 24, or 25, wherein the medicament is for treating, stabilizing or preventing cancer in a mammal.

27. The use according to claim 26, wherein said cancer is a breast cancer, colon carcinoma, colorectal carcinoma, neuroblastoma, or glioma.

28. The use according to any one of claims 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, wherein the mammal is a human.

44. A kit for the use according to any one of claims 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, or the method according to any one of claims 41, 42, or 43, comprising an inhibitor of methylenetetrahydrofolate reductase (MTHFR) which selectively inhibits cancer cell growth, wherein the inhibitor reduces MTHFR gene expression or MTHFR activity.

35. A non-allele specific antisense oligonucleotide at least 7 nucleotides in length that comprises a sequence that is complementary to a gene encoding human methylenetetrahydrofolate reductase (MTHFR), wherein the oligonucleotide inhibits human MTHFR gene expression.

36. The antisense oligonucleotide according to claim 35, wherein the antisense oligonucleotide selectively inhibits cancer cell growth.

37. The antisense oligonucleotide according to claim 35 or 36, wherein the antisense oligonucleotide is complementary to exon 5 of the MTHFR gene.

38. The antisense oligonucleotide according to any one of claims 35, 36, or 37, wherein the oligonucleotide comprises a sequence as set forth in SEQ ID NO:

16.

39. The antisense oligonucleotide according to any one of claims 35, 36, 37, or 38, wherein the oligonucleotide is a phosphorothioate nucleic acid.

40. A vector comprising a nucleic acid encoding the antisense oligonucleotide according to any one of claims 35, 36, 37, 38, or 39.

41. A method of treating stabilizing or preventing cancer in a mammal comprising the step of selectively inhibiting cancer cell growth in the mammal by administering an inhibitor of methylenetetrahydrofolate reductase (MTHFR), wherein the inhibitor reduces MTHER gene expression or MTHFR activity.

42. The method according to claim 41, wherein said mammal is a human.

43. A method of inhibiting growth of cancer cells comprising the step of contacting said cancer cells with an inhibitor of methylenetetrahydrofolate reductase (MTHFR), wherein the inhibitor reduces MTHFR gene expression or MTHFR activity.