Compositions and methods for use in targeting vascular destruction
View Patent ↗Treatment of warm-blooded animals having a tumor or non-malignant hypervascularation, by administering a sufficient amount of a cytotoxic agent formulated into a phosphate prodrug form having substrate specificity for microvessel phosphatases, so that microvessels are destroyed preferentially over other normal tissues, because the less cytotoxic prodrug form is converted to the highly cytotoxic dephosphorylated form.
1. A method for inhibiting tubulin polymerization, comprising contacting a cell with an effective amount of the compound of Formula I:
wherein X is NH or S, and;
R a is hydroxyl or phosphate, thereby inhibiting tubulin polymerization.
2. method of claim 1 , wherein the compound further comprises enantiomers or racemic mixtures of the compound, or pharmaceutically acceptable salts thereof.
3. The method of claim 1 , wherein the phosphate has the following formula Ia:
wherein
X is O;
Y is O, NH, S, O − , NH − , or S − ;
Z is O or S; and
each of R 1 and R 2 is an alkyl group, H, a mono- or divalent cationic salt, or an ammonium cationic salt, and R 1 and R 2 may be the same of different.
4. The method of claim 3 , wherein the phosphate has the following structure:
5. The method of claim 1 , wherein the cell is a tumor cell or vascular endothelial cell.
6. A method for destroying proliferating vasculature comprising administering to a locality of proliferating vasculature, an effective amount of the compound of Formula I:
wherein X is NH or S, and;
R a is hydroxyl or phosphate, or enantiomers or racemic mixtures or pharmaceutically acceptable salts thereof, thereby destroying the proliferating vasculature.
7. The method of claim 6 , wherein the phosphate has the following Formula Ia:
wherein
X is O;
Y is O, NH, S, O − , NH − , or S − ;
Z is O or S; and
each of R 1 and R 2 is an alkyl group, H, a mono- or divalent cationic salt, or an ammonium cationic salt, and R 1 and R 2 may be the same of different.
8. The method of claim 6 , wherein the phosphate has the following structure:
9. The method of claim 6 , wherein the proliferating vasculature is malignant.
10. The method of claim 9 , wherein the malignant proliferating vasculature is a tumor vasculature.
11. The method of claim 6 , wherein the locality of proliferating vasculature is located in a mammal afflicted with a malignant vascular proliferative disorder.
12. The method of claim 11 , wherein the locality of proliferating vasculature is associated with a tumor.
13. The method of claim 12 , wherein the malignant proliferative disorder is selected from the group consisting of Kaposi's sarcoma, leukemia, lymphoma, lung cancer, colon cancer, ovarian cancer, melanoma, prostate cancer, and breast cancer.
14. The method of claim 6 , wherein the proliferating vasculature is nonmalignant.
15. The method of claim 6 , where the locality of proliferating vasculature is located in a mammal afflicted with a nonmalignant vascular proliferative disorder.
16. The method of claim 15 , wherein the nonmalignant vascular proliferative disorder is psoriasis, restenosis, or macular degeneration.