Taxol, the first of an important new class of chemotherapeutic compounds, is highly-promising for a variety of malignancies, including refractory ovarian and breast cancer. However, efficacy is limited by delayed and acute toxicity. Myelosuppression, peripheral and sensory neuropathy, gastrointestinal epithelial necrosis, and alopecia are examples of delayed toxicity. Acute toxicity arises from the low solubility of taxol in water, which necessitates administration in Cremophor EL (polyethoxylated castor oil), an excipient that causes life-threatening hypersensitivity reactions (HSR). Severe pain is an additional dose-limiting toxicity hindering the use of this otherwise-promising agent in regional therapy (eg. i.p. for ovarian cancer). Prophylaxis against HSR involves slow drug infusion and premedication with antihistamines and glucocorticoids. Conceivably, pharmacokinetics and therapeutics of taxol may be complicated by interactions of the premedication regimen. We have developed taxol-liposome (T-lip) formulations that eliminate acute toxicity, reduce chronic toxicity, and in some cases enhance antitumor activity of taxol. The formulations are prepared in the lyophilized state, providing a scaleable, pharmaceutically-rational dosage form. Mice tolerate bolus i.v. doses of equal to or more than 5O mg/kg (or equal to or greater than 2OO mg/kg in split doses over 4 h), whereas conventional taxol is lethal at equal to or greater than 35 mg/kg. Delayed toxicity likewise is reduced, with a 2-7-fold increase in Maximum Tolerated Dose (MTD) for T-lip. Cumulative doses of 360 mg/kg T-lip were tolerated, whereas 180 mg/kg free taxol was lethal. Antitumor potency of T-lip formulations was tested against subcutaneous (s.c.) taxol-resistant murine Colon-26 (C-26), human ovarian tumors (A121a), and primary human lung tumors, as well as i.p. P388 leukemia. Potency of T-lip equals or exceeds that of free drug; against C-26, no dose of free taxol had a discernible effect, up to a lethal cumulative dose. In contrast, T-lip showed a significant reduction in tumor growth at doses equal to or greater than the MTD of free taxol. We have also developed formulations of other taxanes, with similar retention of antitumor effect. We have two main objectives: (l) investigate the pharmacology and pharmaceutics of existing T-lip formulations to determine the mechanism by which beneficial effects have been obtained; (2) develop new formulations, either optimized in general or for specific applications. Essential to achieving (1) is a comprehensive investigation of taxol biopharmaceutics. Efforts relating to T-lip pharmacology will investigate mechanisms responsible for the observed increase in MTD and efficacy. Pharmacokinetic approaches will be used to investigate the mechanisms of drug transport to tumor and tissues, and the stability of the drug:liposome complex in vivo. Physiologic pharmacodynamic models for T- lip action are the eventual objective of these studies. Objective (2), development of new formulations, builds on extensive ongoing biophysical studies, and includes aims to increase taxol content of T-lip, extend their circulating half-life, increase the deposition of drug in tumors, and investigate alternate technologies for production of T-lip with specific properties.
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