We seek to improve the efficacy of a promising anticancer agent, taxol, by reformulation in a carrier-based system. Ongoing clinical trials show activity of taxol in the treatment of refractory human ovarian cancer,melanoma, and others. Dose-limiting side effects of taxol include myelosuppression, non-hematologic effects such as peripheral neuropathy, and alopecia; life-threatening epithelial necrosis in the gastrointestinal (GI) tract also has been noted. In addition to toxicity of the Cremophor vehicle, taxol is given by prolonged infusion; this limits not only comfort and convenience to the patient, but, more importantly, limits the opportunities for widening the taxol therapeutic index through alterations in route and schedule of administration that could optimize taxol pharmacokinetics. Several modern drug carrier systems, including cyclodextrins, polyethylene glycols, and lipid vesicles (liposomes), presently are under evaluation to reduce dose-limiting side effects of anticancer agents. Among these carriers, liposomes represent a mature, versatile technology for improved solubilization of lipophilic drugs such as adriamycin (ADR), Amphotericin B, and cyclosporine. ADR:liposome formulations have been examined in Phase I human trials, and show a reduction in ADR toxic side effects, particularly myelosuppression, epithelial necrosis in the GI tract, and alopecia. Human pharmacokinetic studies also reveal a reduction in biotransformation of liposome-encapsulated ADR to a metabolite believed to be inactive. Thus the reduced toxicity observed in clinical trials suggest the feasibility of further dose escalation for AFR reformulated in a liposome carrier system, as well as a prolonged circulation time for active drug. We propose to develop carrier formulations of taxol, with the primary aim of eliminating the toxic effects attributed to the Cremophor vehicle, and the secondary aim of modulating the toxicity, and perhaps the pharmacology, of taxol itself. First priority is given to optimizing formulations of taxol:liposomes already identified in preliminary studies; second priority is given to developing new-generation carrier formulations such as taxol:cyclodextrins, which may be more amenable to large-scale pharmaceutical production, and which may possess additional unique pharmacological properties. The development scheme first will evaluate cytostatic and cytotoxic potency of taxol formulations in vitro, on human ovarian cancer cell lines, and a murine melanoma and colon carcinoma. Sexond, we will optimize antitumor activity of the taxol:carrier formulations in murine tumor systems, and subsequently evaluate efficacy against a human ovarian tumor in athymic nude mice. Third, we will examine whether carrier formulations alter the pharmacokinetics and tissue distribution of active taxol.
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