Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders

• US 6,521,608 B1
• Filed: 09/21/2000
• Issued: 02/18/2003
• Est. Priority Date: 03/27/1998
• Status: Expired due to Term

• Current Assignee: Oregon Health & Science University
• Original Assignee: Oregon Health & Science University
• Inventors: Henner, William D., Beer, Tomasz M.
• Primary Examiner(s): Criares, Theodore J.
• Assistant Examiner(s): KIM, JENNIFER M
• Application Number:
  US09/647,075
• Time in Patent Office: 880 Days
• Field of Search: 514/167, 514/168
• US Class Current: 514/167
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia

Abstract

Treatment of hyperporliferative disorders (including tumors and psoriasis) by pulse administration of a drug (such as Vitamin D or an analog) that increases blood or tissue levels of Vitamin D. The drug is administered at a sufficient dose to have an anti-proliferative effect, but the pulsed administration of the drug avoids the development of severe symptomatic or life-threatening hypercalcemia. In particular embodiments, avoidance of hypercalcemia (as measured by serum levels of calcium above normal range) is avoided altogether. In a particular example, the drug is calcitriol administered at an oral dose of about 0.5 mcg/kg once a week.

Claims

1. A method for the treatment of a hyperproliferative disease in a subject, wherein the hyperproliferative disease responds to treatment with a Vitamin D drug, comprising repeatedly administering to the subject a therapeutically effective pulse dose of the Vitamin D drug, no more frequently than once in three days, in a pulse dose of about 0.12 mcg/kg per day to about 2.8 mcg/kg per day, each pulsed dose being in a sufficient amount to have an antiproliferative effect, without inducing severe symptomatic hypercalcemia in the subject, wherein the Vitamin D drug is 25-hydroxyvit D₃ or 1,25-dihydroxycholecalciferol.

2. The method of claim 1, comprising administering the Vitamin D drug to a subject having a neoplasm that expresses a Vitamin D receptor, wherein the therapeutically effective pulse dose is an anti-neoplastic dose.

3. The method of claim 2, wherein the neoplasm is selected from the group of cancer of the prostate, breast, colon, lung, head ad neck, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, renal cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thryoid carcinoma, melanoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissues and bone.

4. The method of claim 3, wherein the neoplasm is breast cancer or prostate cancer.

5. The method of claim 1, wherein each dose of the Vitamin D drug is administered in an amount that raises a serum level of the Vitamnin D drug in the subject with a tumor to a supraphysiologic amount for a sufficient period of time to induce differentiation or regression of the tumor without causing symptomatic hypercalcemia.

6. The method of claim 1, wherein the Vitamin D drug is calcitriol, which is administered in a therapeutically effective pulse dose no more than once in five days.

7. The method of claim 6, wherein the calcitriol is administered orally in a dose of at least 0.12 mcg/kg per day no more than once in five days.

8. The method of claim 6, wherein the calcitriol is administered orally in a dose of at least 0.48 mcg/kg or about 1 mcg/kg per day no more than once in a week.

11. The method of claim 1, wherein the subject eats a reduced calcium diet for a sufficient period of time prior to administration of the Vitamin D drug to reduce absorption of dietary calcium.

21. The method according to claim 1 wherein the hyperproliferative disorder comprises a hyperproliferative skin disease.

22. The method according to claim 21 wherein the hyperproliferative skin disease is selected from the group consisting of psoriasis, disorders of keratinization, keratosis, disorders of sebaceous glands, and combinations thereof.

23. The method according to claim 22 wherein the hyperproliferative skin disease comprises disorders of sebaceous glands.

54. The method of claim 1, wherein the Vitamin D drug is calcitriol, which is administered in a dosage form that contains 5-100 mcg calcitriol.

9. A method of treating a tumor in a subject, wherein the tumor expresses a Vitamin D receptor and is responsive to treatment with a Vitamin D drug, the method comprising repeatedly administering orally to the subject, once in a three to ten day period, a dose of calcitriol, wherein each dose of calcitriol is a therapeutically effective dose, of about 0.12 mcg/kg to about 2.8 mcg/kg, sufficient to have an antiproliferative effect, without inducing severe symptomatic hypercalcemia in the subject.

10. The method of claim 9, wherein the calcitriol is administered to the subject no more than once per week.

12. A method of treating in a subject a tumor that expresses a Vitamin D receptor, the method comprising repeatedly administering a dose of a Vitamin D drug to raise a blood level of the Vitamin D drug to a sufficiently supraphysiologic level for a sufficient period of time to inhibit growth of the tumor, wherein each dose of the Vitamin D drug is sufficient to inhibit tumor growth without inducing hypercalcemia in the subject, wherein the Vitamnin D drug is 25-hydroxyvitamin D₃ or 1,25-dihydroxycholecalciferol and the dose is administered no more than once in 3-10 days, and wherein the Vitamin D drug is admistered in a dose of about 0.12 mcg/kg per day to about 2.8 mcg/kg per day.

13. The method of claim 12, wherein the Vitamin D drug comprises calcitriol.

14. The method of claim 13, wherein the calcitriol is administered in a dose of about 0.50 mcg/kg per day once per week.

15. A method of administering a Vitamin D drug to a subject in need thereof, the method comprising repeatedly administering therapeutically effective pulse doses of the Vitamin D drug wherein each dose is sufficient to achieve intermittent antiproliferative therapeutic levels of the Vitamin D drug, and wherein the pulse doses are administered separated by 3-10 days to avoid symptomatic hypercalcemia, and wherein each dose is about 0.12 mcg/kg per day to about 2.8 mcg/kg per day and the Vitamin D drug is 25-hydroxyvitamin D₃ or 1,25-dihydroxycholecalciferol.

16. The method of claim 15, wherein the method comprises treating a hyperproliferative disorder in the subject.

17. The method according to claim 16 wherein the hyperproliferative disorder is a hyperproliferative skin disease.

18. The method according to claim 17 wherein the hyperproliferative skin disease is selected from the group consisting of psoriasis, disorders of keratinization, keratosis, disorders of sebaceous glands, and combinations thereof.

19. The method according to claim 18 wherein the hyperproliferative skin disease comprises disorders of sebaceous glands.

20. The method of claim 19, wherein the hyperproliferative skin disease comprises acne or sebonheic dermatitis.

24. The method of claim 19, wherein the hyperproliferative skin disease comprises acne or seborrheic dermatitis.

25. The method of claim 15, wherein each dose of the Vitamin D drug achieves a serum level of about 0.5-25 nM of the drug.

26. The method of claim 25, wherein each dose of the Vitamin D drug achieves a serum level of about 1-25 nM of the drug.

27. The method of claim 25, wherein each dose of the Vitamin D drug achieves a serum level of about 5-10 nM of the drug.

28. The method of claim 15, wherein the drug is administered in a dose of at least 0.12 mcg/kg per day no more than once every 5 or 6 days.

29. The method of claim 28, wherein the drug is administered no more than once a week.

30. The method of claim 29, wherein the drug is administered in a dose of at least 0.48 mcg/kg per day no more than once per week.

31. The method of claim 30, wherein the drug is administered in a dose of about 2.80 mcg/kg per day.

32. The method of claim 29, wherein the drug is administered in a dose of about 0.24 to about 2.80 mcg/kg per day.

33. The method of claim 15, wherein the drug is administered orally, intravenously, parenterally, rectally, topically, nasally or transdermally.

34. The method of claim 33, wherein the drug is admitered orally.

35. The method of claim 15, wherein the drug is administered in conjunction with an other therapeutic agent.

36. The method of claim 35, wherein the other therapeutic agent is an osteoclast inhibitor.

37. The method of claim 36, wherein the osteoclast inhibitor comprises a biphosphonate osteoclast inhibitor.

38. The method of claim 15, wherein the method further comprises administering to the subject an initial dose of the drug, followed by a series of pulsed administrations of an escalated dose, wherein each pulsed administration is in an amount sufficient to have an antiproliferative effect, and wherein each subsequent administration follows the preceding administration by a period of time sufficient to avoid symptomatic hypercalcemia in the subject.

39. The method of claim 15, wherein serum levels of calcium return to normal levels of calcemia between doses of the drug.

40. The method of claim 15, wherein the drug would induce hypercalcemia if administered daily at the dose at which it is administered in pulse doses separated by 3-10 days.

50. The method of claim 15, wherein the pulse dose is administered in divided doses over a one day period.

52. The method of claim 15, wherein each pulse dose is administered as a single dose.

41. A method of administering a Vitamin D drug to a subject at an anti-hyperproliferative dose substantially without symptomatic significant hypercalcemia, wherein the method comprises repeatedly administering therapeutically effective pulsed doses of the Vitamin D drug, wherein each dose of the Vitamin D drug is a dose that is sufficient to have an antiproliferative effect, the dose is repetitively administered separated by 3-10 days, and the Vitamin D drug is calcitriol, and wherein the dose is about 0.12 mcg/kg per day to about 2.8 mcg/kg per day.

42. The method of claim 41, wherein each dose of the drug is sufficient to have an anti-tumor antiproliferative effect.

43. The method of claim 42, wherein the dose of the drug is sufficient to raise a serum level of the drug to 0.5-25 nM.

44. The method of claim 42, wherein the dose of the drug is about 0.48-2.80 mcg/kg.

45. The method of claim 42, comprising administering the Vitamin D drug to a subject having a neoplasm that expresses a Vitamin D receptor.

46. The method of claim 42, wherein the neoplasm is selected from the group of cancer of the prostate, breast, colon, lung, head and neck, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, renal cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thryoid carcinoma, melanoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissues and bone.

47. The method of claim 44, wherein the dose is administered orally.

48. The method of claim 41, wherein the doses are separated by 7-10 days.

49. The method of claim 43, wherein the dose of the drug is sufficient to raise the serum level of the drug to 0.5-25 nM for no more than about 6 hours.

51. The method of claim 41, wherein each pulse dose is administered in divided doses over a one day period.

53. The method of claim 41, wherein each pulse dose is administered as a single dose.