DNA DAMAGING AGENTS IN COMBINATION WITH TYROSINE KINASE INHIBITORS

• US 20060251734A1
• Filed: 05/02/2006
• Published: 11/09/2006
• Est. Priority Date: 02/04/1994
• Status: Active Grant

• Current Assignee: Donald Kufe, Ralph R. Weichselbaum
• Original Assignee: Donald Kufe, Ralph R. Weichselbaum
• Inventors: KUFE, DONALD, WEICHSELBAUM, RALPH R.
• Granted Patent: US 7,838,512 B2
• Time in Patent Office: Days
• US Class Current: 424/649
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 41/0023 Agression treatment or altering
• CPC Class Codes: A61K 41/17 by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence

Abstract

The present invention relates to the signalling pathways connecting DNA damage, such as that induced by ionizing radiation or alkylating agents, and phosphorylation by tyrosine kinases.

Claims

1-21. -21. (canceled)

22. A method of treating cancer comprising the steps of:

administering a DNA damaging agent, and

administering a low molecular weight agent that intracellularly inhibits tyrosine kinase activity of a protein tyrosine kinase.

23. The method of claim 22, wherein said protein tyrosine kinase is a receptor protein tyrosine kinase.

24. The method of claim 23, wherein said receptor protein tyrosine kinase is EGFR.

25. The method of claim 22, wherein said protein tyrosine kinase is a non-receptor protein tyrosine kinase.

26. The method of claim 25, wherein said non-receptor protein tyrosine kinase is fyn, lck, lyn, blk or src.

27. The method of any of claims 22, 23, 24, 25, or 26, wherein said DNA damaging agent is a chemical.

28. The method of claim 27, wherein said chemical is a genotoxic alkylating agent.

29. The method of claim 27, wherein said chemical is a DNA cross-linker.

30. The method of claim 27, wherein said chemical is a DNA intercalator.

31. The method of claim 27, wherein said chemical is a chromosomal segregation inhibitor.

32. The method of claim 27, wherein said chemical is a DNA replication inhibitor.

33. The method of claim 27, wherein said chemical is a nucleic acid precursor.

34. The method of claim 27, wherein said chemical is mitomycin C.

35. The method of claim 27, wherein said chemical is adozelesin.

36. The method of claim 27, wherein said chemical is cisplatin.

37. The method of claim 27, wherein said chemical is nitrogen mustard.

38. The method of claim 27, wherein said chemical is adriamycin.

39. The method of claim 27, wherein said chemical is etoposide.

40. The method of claim 27, wherein said chemical is verapamil.

41. The method of claim 27, wherein said chemical is podophyllotoxin.

42. The method of claim 27, wherein said chemical is 5-fluorouracil.

44. The method of any of claims 22, 23, 24, 25 or 26, wherein said DNA damaging agent is radiation.

45. The method of claim 44, wherein said radiation is ionizing radiation such as x-rays, uv-light, γ

-rays or microwaves.

46. The method of any of claims 27 or 44, wherein said cancer is colon cancer, stomach cancer, pancreatic cancer, cancer of the oral cavity, breast cancer, or cancer of the head &

neck.

47. A method of treating cancer cells comprising administering chemotherapy with a low molecular weight agent that intracellulary inhibits the autophosphorylation of EGFR.

48. The method of claim 47, wherein said chemical is a genotoxic alkylating agent.

49. The method of claim 47, wherein said chemical is a DNA cross-linker.

50. The method of claim 47, wherein said chemical is a DNA intercalator.

51. The method of claim 47, wherein said chemical is a chromosomal segregation inhibitor.

52. The method of claim 47, wherein said chemical is a DNA replication inhibitor.

53. The method of claim 47, wherein said chemical is a nucleic acid precursor.

54. A method of treating pancreatic cancer cells comprising administering chemotherapy with an agent having a low molecular weight that intracellularly inhibits the autophosphorylation of EGFR.

55. The method of claim 54, wherein said chemical is a genotoxic alkylating agent.

56. The method of claim 54, wherein said chemical is a DNA cross-linker.

57. The method of claim 54, wherein said chemical is a DNA intercalator.

58. The method of claim 54, wherein said chemical is a chromosomal segregation inhibitor.

59. The method of claim 54, wherein said chemical is a DNA replication inhibitor.

60. The method of claim 54, wherein said chemical is a nucleic acid precursor.

61. The method of claim 54, whereby the cancer cells are unable to arrest.

62. The method of any of claims 54 or 61, whereby the cancer cells are unable to arrest at the G2 phase of the cell cycle.

63. A method of treating pancreatic cancer comprising:

administering chemotherapy with an agent having a low molecular weight that intracellularly inhibits the autophosphorylation of a protein tyrosine kinase.

64. A method of treating pancreatic cancer comprising:

administering chemotherapy with an agent having a low molecular weight that intracellularly inhibits the autophosphorylation of EGFR.

65. A method of treating cancer cells comprising:

administering chemotherapy with a low molecular weight agent that intracellularly inhibits the autophosphorylation of a protein tyrosine kinase whereby the cells are unable to arrest.

66. The method of claim 65, whereby the cells are unable to arrest at the G2 phase of the cell cycle.