Method of inhibiting angiogenesis using active vitamin D analogues

• US 6,573,256 B2
• Filed: 06/26/2001
• Issued: 06/03/2003
• Est. Priority Date: 12/30/1996
• Status: Expired due to Fees

• Current Assignee: Bone Care International LLC
• Original Assignee: Bone Care International LLC
• Inventors: Bishop, Charles W., Mazess, Richard B.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/891,805
• Publication Number:
  US 20020019375A1
• Time in Patent Office: 707 Days
• Field of Search: 514/168, 514/167
• US Class Current: 514/168
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems

Abstract

Methods utilizing active vitamin D analogs for the inhibition of angiogenesis associated with malignant and neoplasmic cells. Methods comprise the application of an effective amount of a hypocalcemic vitamin D compound to inhibit the angiogenesis of malignant cells, inducing the apoptosis of malignant cells, and regressing the growth of tumorous cells.

Claims

1. A method of inhibiting angiogenesis associated with malignant or neoplastic cells, comprising treating the cells with an effective amount of a hypocalcemic hydroxy vitamin D compound having a hydrocarbon moiety at the C₂₄ position, the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinomas, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.

2. A method of inhibiting angiogenesis associated with malignancy or neoplasm in a subject in need thereof, comprising administering to the subject an effective amount of a hypocalcemic vitamin D compound represented by formula I:

wherein A¹ and A² each are hydrogen or a carbon—

carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃-C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, and X² is hydrogen or hydroxyl, or, may be taken with R¹ or R², to constitute a double bond, and X³ is hydrogen or hydroxyl provided that at least one of X¹, X² and X³ is hydroxyl; and

Y is a methylene group if the bond to Y is a double or is a methyl group or hydrogen if the bond to Y is a single bond sufficient to inhibit angiogenesis of the malignancy or neoplasm.

3. A method in accordance with claim 2, wherein the hypocalcemic vitamin D compound is represented by formula II:

wherein A¹ and A²each are hydrogen or a carbon—

carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃-C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, and X² is hydrogen or hydroxyl, or, may be taken with R¹ or R², to constitute a double bond, and Y is a methylene group if the bond to Y is a double or is a methyl group or hydrogen if the bond to Y is a single bond.

4. The method of claim 2, wherein said hypocalcemic vitamin D is a 1α

-hydroxyvitamin D compound is represented by formula III;

wherein A¹ and A² each are hydrogen or a carbon—

carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃-C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, and X² is hydrogen or hydroxyl, or, may be taken with R¹ or R², to constitute a double bond.

5. The method of claim 4, wherein the compound of formula (I) is 1α

,24-dihydroxyvitamin D₂, 1α

,24-dihydroxyvitamin D₄, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

-hydroxyvitamin D₂ or 1α

-hydroxyvitamin D₄.

6. A method in accordance with claim 2, wherein a dosing regimen for the hypocalcemic vitamin D compound is a daily regimen or an episodic regimen.

7. A method in accordance with claim 6, wherein the espisodic regimen is a dose once every 2 to 7 days.

8. A method in accordance with claim 6, wherein the hypocalcemic vitamin D compound is administered daily at a dose of about 10 to 100 μ

g/day.

9. A method in accordance with claim 6, wherein the hypocalcemic vitamin D compound is administered orally, is administered intravenously, is injected directly into a cancer site, or is regionally delivered to a cancer site.

10. A method in accordance with claim 9, wherein the hypocalcemic vitamin D compound is administered orally.

11. A method in accordance with claim 2, wherein the hypocalcemic vitamin D compound is co-administered with a cytotoxic agent.

12. A method in accordance with claim 11, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.

13. A method in accordance with claim 12, wherein the antimetabolite is 5-fluorouracil, methotrexate or fludarabine.

14. A method in accordance with claim 12, wherein the antimicrotubule agent isvincristine, vinblastine or a taxane.

15. A method in accordance with claim 11, wherein the taxane is paclitaxel or docetaxel.

16. A method in accordance with claim 12, wherein the alkylating agent is cyclophasphamide, melphalan, biochoroethylnitrosurea or hydroxyurea.

17. A method in accordance with claim 12, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, JM-216 or CI-973.

18. A method in accordance with claim 12, wherein the anthracycline is doxrubicin or daunorubicin.

19. A method in accordance with claim 12, wherein the antibiotic is mitomycin, idarubicin, adriamycin or daunomycin.

20. A method in accordance with claim 12, wherein the topoisomerase inhibitior is etoposide or camptothecins.

21. A method in accordance with claim 12, wherein the cytotoxic agent is estramustine phosphate or prednimustine.

22. A method of treating a human to inhibit angiogenesis associated with breast cancer, colon cancer, prostate cancer, testicular cancer, pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma or sarcomas of the soft tissue and bone, comprising administering to the human an effective amount of a hypocalcemic vitamin D compound.

23. A method of claim 22, wherein said hypocalcemic vitamin D is a 1α

-hydroxyvitamin D compound represented by formula III;

wherein A¹ and A² each are hydrogen or a carbon—

carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃-C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, and X² is hydrogen or hydroxyl, or, may be taken with R¹ or R², to constitute a double bond.

24. The method of claim 23, wherein said therapeutic amount is 0.01 μ

g/kg/day to 2.0 μ

g/kg/day.

25. The method of claim 23, wherein the compound of formula (I) is 1α

,24-dihydroxyvitamin D₂, 1α

,24-dihydroxyvitamin D₄,1α

25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

-hydroxyvitamin D₂ or 1α

-hydroxyvitamin D₄.

26. A method of treating a human to inhibit angiogenesis associated with malignant cells, comprising administering to the patient a hypocalcemic vitamin D compound and a cytotoxic agent.

27. A method in accordance with claim 26, wherein the hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of the cytotoxic agent.

28. A method in accordance with claim 26, wherein the hypocalcemic vitamin D compound is administered 2 to 4 days prior to administration of the cytotoxic agent.

29. A method of claim 26, wherein said hypocalcemic vitamin D is a 1α

-hydroxyvitamin D compound represented by formula III;

wherein A¹ and A² each are hydrogen or a carbon—

carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃-C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, or, taken with R³, constitutes a bond when R³ is an alkenyl group, and X² is hydrogen or hydroxyl, or, taken with R¹ or R², constitutes a double bond.

30. The method of claim 29, wherein said therapeutic amount is 0.01 μ

g/kg/day to 2.0 μ

g/kg/day.

31. The method of claim 29, wherein the compound of formula (I) is 1α

,24-dihydroxyvitamin D₂, 1α

,24-dihydroxyvitamin D₄, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

-hydroxyvitamin D₂ or 1α

-hydroxyvitamin D₄.

32. A method in accordance with claim 29, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.

33. A method of inducing apoptosis of malignant or neoplastic cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound, the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.

34. A method of inducing the regression of tumor cells comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound, which inhibits angeogenesis associated with malignancy the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.