Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-12-12
2000-06-27
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
424 11, 435366, 435375, A61K 4300, A01N 4302
Patent
active
060807776
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referred to within parenthesis. Full bibliographic citations for these references may be found at the end of the specification, immediately preceding the claims. The disclosures for these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the art to which this invention pertains.
Taxol is the prototype of a new class of antineoplastic agents that targets microtubules. It is a natural product isolated from the bark of the western yew, Taxus brevifolia. Its structure, a novel diterpene compound, and antitumor activity in rodents were reported in 1971 (16). The drug's unique mechanism of action has generated considerable interest, both for its use to probe the function of the cytoskeleton in basic science, and as a chemotherapeutic agent in oncology. Taxol is known to be a potent cytotoxic agent against a range of human malignancies using cell culture and xenographic model systems (9). Human studies have demonstrated taxol's ability to increase the mitotic index in a variety of tissues (4). Clinical trials have demonstrated that taxol is an active agent in salvage treatment for epithelial ovarian malignancies (2, 5, 15) and has activity against breast cancer (3) as well as melanoma (7, 18).
Unlike agents that bind to tubulin, the subunit of microtubules, and inhibit microtubule formation (vinca alkaloids, podophyllotoxin, and colchicine), taxol induces in vitro formation of exceptionally stable microtubules (10). Tissue and culture studies have shown the ability of taxol to block and/or prolong cells in the G2 or M phase of the cell cycle (11). The microtubule cytoskeletons of taxol-treated cells are exceedingly stable to depolymerization, as are isolated drug-treated microtubules. In addition, electron microscopy reveals an abnormal microtubular cytoskeleton in drug-treated cells. The inability of these cells to pass through the G2 and M phases of the cell cycle probably results from the inability of these cells to form a competent mitotic spindle or to disassociate a drug-treated spindle. Taxol additionally blocks the migration behavior of cells in culture. These observations may explain the observed antitumor activity of the drug.
Taxol has undergone several Phase I trials at many institutions (9). Plasma concentrations of 1 nM to 5 .mu.M taxol at safe therapeutic doses are comparable to those required for the antiproliferative and microtubule-stabilizing effects of the drug in vitro. Mitotic arrest has been observed in the esophagus, stomach, small intestine, colon, liver, skin, bone marrow, and testes of patients biopsied within 11 days after receiving taxol (4). Dose-limiting toxicity includes leukopenia, thrombocytopenia, alopecia, nausea and vomiting, diarrhea, stomatitis, peripheral neuropathy, rashes, elevated serum triglyceride levels, and severe hypersensitivity (most likely related to the cremophor vehicle) (1, 5, 6, 17, 18). Partial responses have been reported in patients with non-small cell lung cancer, melanoma, and ovarian cancer. One Phase II study has reported significant activity against standard drug protocol refractory ovarian cancer (8).
It is well known from radiobiological principles that G2/M is the most radiosensitive phase of the cell cycle (13). However, use of taxol, related compounds or pharmaceutically acceptable salts thereof to enhance the cytotoxic effect of ionizing radiation has not previously been described.
SUMMARY OF THE INVENTION
This invention provides a method of increasing the sensitivity of cells to the cytotoxic effects of ionizing radiation which comprises first incubating the cells with a spindle poison in a suitable carrier at a concentration effective to inhibit the cells from progressing through the G2 or M phases of the cell cycle for an amount of time effective to inhibit division of the cells and then administering an effective cytotoxic dose of ionizing radiation to the cells.
This invention also p
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Spivack Phyllis G.
The Trustees of Columbia University in the City of New York
White John P.
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