Combination chemotherapy

• US 20030216359A1
• Filed: 05/05/2003
• Published: 11/20/2003
• Est. Priority Date: 08/29/1997
• Status: Abandoned Application

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Trump, Donald L., Johnson, Candace S.
• Application Number:
  US10/429,840
• Publication Number:
  US 20030216359A1
• Time in Patent Office: Days
• US Class Current: 514/168
• 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 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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

This invention relates to combination chemotherapy, particularly involving vitamin D or a derivative thereof. In one aspect, the invention provides a method of killing a cell by first administering to the cell vitamin D (or a derivative) and subsequently administering to the cell a cytotoxic agent. Where this strategy is applied to an intact tumor, the present invention provides a method of retarding the growth of the tumor by first administering vitamin D (or a derivative) to the tumor and subsequently administering the cytotoxic agent. A further aspect of the invention concerns a method of treating prostate cancer within a patient by co-administration of vitamin D (or a derivative) and a glucocorticoid to the patient. In yet a further aspect, the invention provides an improved method of treating a patient with vitamin-D involving the adjunctive administration of zoledronate.

Claims

1. A method of killing a cell within a patient comprising the steps of (a) first administering to a cell within the patient vitamin D or a derivative thereof and (b) subsequently administering at least one cytotoxic agent to the cell, wherein the cell is susceptible to said steps (a) and (b).

2. The method of claim 1, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.

3. The method of claim 2, wherein the glucocorticoid is dexamethasone.

4. The method of claim 2, wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.

5. The method of claim 1, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.

6. The method of claim 1, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.

7. The method of claim 1, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.

8. The method of claim 1, wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D₃.

9. The method of claim 8, wherein the analog is Ro23-7553 or Ro24-5531.

10. The method of claim 1, wherein the vitamin D or a derivative thereof is 1,25D₃.

11. The method of claim 1, wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μ

g and about 15 μ

g.

12. The method of claim 11, wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μ

g and about 12 μ

g.

13. The method of claim 1, wherein the cytotoxic agent selectively acts on cells in the G₀-G₁ phase of the cell cycle.

14. The method of claim 1, wherein the cytotoxic agent is a platinum-based cytotoxic agent.

15. The method of claim 1, wherein the cytotoxic agent is a glucocorticoid.

16. The method of claim 1, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.

17. The method of claim 1, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.

18. The method of claim 1, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m².

19. The method of claim 1, wherein said cytotoxic agent is docetaxel.

20. The method of claim 1, wherein the vitamin D or a derivative thereof is 1,25D₃ and wherein said cytotoxic agent is docetaxel.

21. The method of claim 1, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.

22. A method of retarding the growth of a tumor within a patient comprising the steps of (a) first administering to the tumor within the patient a vitamin D or a derivative thereof and (b) subsequently administering to the tumor at least one cytotoxic agent, wherein the cell is susceptible to said steps (a) and (b).

23. The method of claim 22, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.

24. The method of claim 23, wherein the glucocorticoid is dexamethasone.

25. The method of claim 23, wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.

26. The method of claim 22, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.

27. The method of claim 22, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.

28. The method of claim 22, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.

29. The method of claim 22, wherein the vitamin D derivative is a nonhypercalcemic analog of 1,25D₃.

30. The method of claim 29, wherein the analog is Ro23-7553 or Ro24-5531.

31. The method of claim 22, wherein the vitamin D derivative is 1,25D₃.

32. The method of claim 22, wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μ

g and about 15 μ

g.

33. The method of claim 32, wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μ

g and about 12 μ

g.

34. The method of claim 22, wherein the cytotoxic agent selectively acts on cells in the G₀-G₁ phase of the cell cycle.

35. The method of claim 22, wherein the cytotoxic agent is a platinum-based cytotoxic agent.

36. The method of claim 22, wherein the cytotoxic agent is a glucocorticoid.

37. The method of claim 22, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.

38. The method of claim 22, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.

39. The method of claim 22, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m².

40. The method of claim 22, wherein said cytotoxic agent is docetaxel.

41. The method of claim 22, wherein said vitamin D or a derivative thereof is 1,25D₃ and wherein said cytotoxic agent is docetaxel.

42. The method of claim 22, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.

43. A method of treating a human patient with vitamin D or a derivative thereof, wherein the patient has a condition responsive to vitamin D and a cytotoxic agent, comprising the steps of (a) first administering to the patient vitamin D or a derivative thereof and (b) subsequently administering to the patient at least one cytotoxic agent, wherein the dose of the vitamin D or a derivative thereof exceeds 1 μ

g/day.

44. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 4 μ

g/day.

45. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 8 μ

g/day.

46. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 12 μ

g/day.

47. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 18 μ

g/day.

48. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 30 μ

g/day.

49. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 40 μ

g/day.

50. The method of claim 43, wherein the dose of vitamin D or a derivative thereof is at last about 50 μ

g/day.

51. The method of claim 43, wherein the vitamin D or a derivative thereof is administered orally.

52. The method of claim 43, wherein the vitamin D or a derivative thereof is administered intravenously.

53. The method of claim 43, wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.

54. The method of claim 53, wherein the glucocorticoid is dexamethasone.

55. The method of claim 53, wherein the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.

56. The method of claim 43, wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.

57. The method of claim 43, wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.

58. The method of claim 43, wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.

59. The method of claim 43, wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D₃.

60. The method of claim 59, wherein the analog is Ro23-7553 or Ro24-5531.

61. The method of claim 43, wherein the vitamin D or a derivative thereof is 1,25D₃.

62. The method of claim 43, wherein the cytotoxic agent selectively acts on cells in the G₀-G₁ phase of the cell cycle.

63. The method of claim 43, wherein the cytotoxic agent is a platinum-based cytotoxic agent.

64. The method of claim 43, wherein the cytotoxic agent is a glucocorticoid.

65. The method of claim 43, wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.

66. The method of claim 43, wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.

67. The method of claim 43, wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m².

68. The method of claim 43, wherein said cytotoxic agent is docetaxel.

69. The method of claim 43, wherein said vitamin D or a derivative thereof is 1,25D₃ and wherein said cytotoxic agent is docetaxel.

70. The method of claim 43, further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.

71. A method of treating prostate cancer within a patient in need of such treatment comprising adjunctively administering vitamin D or a derivative thereof and a glucocorticoid to the patient.

72. The method of claim 71, wherein the treatment is repeated.

73. The method of claim 71, wherein the vitamin D or a derivative thereof and glucocorticoid are administered to the patient on alternative days between 2 and 4 times a week.

74. The method of claim 71, wherein the glucocorticoid is administered to the patient prior to the administration of the vitamin D or a derivative thereof.

75. The method of claim 71, wherein the glucocorticoid is administered to the patient following the administration of the vitamin D or a derivative thereof.

76. The method of claim 71, wherein the vitamin D derivative is a nonhypercalcemic analog.

77. The method of claim 71, wherein the vitamin D derivative is 1,25D₃.

78. The method of claim 71, wherein the glucocorticoid is selected from the group of glucocorticoids consisting of cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

79. The method of claim 71, wherein the glucocorticoid is dexamethasone.

80. The method of claim 71, further comprising administering at least one bisphosphonate to the cell selected from the group of bisphosphonates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.