Method of inhibiting angiogenesis using active vitamin D analogues
First Claim
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.
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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.
81 Citations
34 Claims
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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.
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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:
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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.- View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
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.
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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.
- -hydroxyvitamin D compound is represented by formula III;
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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.
- ,24-dihydroxyvitamin D2, 1α
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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.
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7. A method in accordance with claim 6, wherein the espisodic regimen is a dose once every 2 to 7 days.
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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.
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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.
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10. A method in accordance with claim 9, wherein the hypocalcemic vitamin D compound is administered orally.
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11. A method in accordance with claim 2, wherein the hypocalcemic vitamin D compound is co-administered with a cytotoxic agent.
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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.
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13. A method in accordance with claim 12, wherein the antimetabolite is 5-fluorouracil, methotrexate or fludarabine.
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14. A method in accordance with claim 12, wherein the antimicrotubule agent isvincristine, vinblastine or a taxane.
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15. A method in accordance with claim 11, wherein the taxane is paclitaxel or docetaxel.
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16. A method in accordance with claim 12, wherein the alkylating agent is cyclophasphamide, melphalan, biochoroethylnitrosurea or hydroxyurea.
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17. A method in accordance with claim 12, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, JM-216 or CI-973.
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18. A method in accordance with claim 12, wherein the anthracycline is doxrubicin or daunorubicin.
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19. A method in accordance with claim 12, wherein the antibiotic is mitomycin, idarubicin, adriamycin or daunomycin.
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20. A method in accordance with claim 12, wherein the topoisomerase inhibitior is etoposide or camptothecins.
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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.
- 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.
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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.
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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.
Specification