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Preclinical Pharmacology of BMS-275183, an Orally Active Taxane

Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, New Jersey 08543 [W. C. R., B. H. L., C. R. F., F. Y. F. L.] and Wallingford, Connecticut 06492 [J. F. K.]

BMS-275183 is a taxane, the mechanism of action of which is like other known taxanes, and is the polymerization of tubulin. BMS-275183 given p.o. was as effective as i.v. paclitaxel in five tumor models [murine M109 lung and C3H mammary 16/C, and human A2780 ovarian (grown in mice and rats) and HCT/pk colon]. It was active in one other tumor model (human HCT-116 colon) but inferior to parenteral paclitaxel. BMS-275183 given p.o. was active in a human, hormone-dependent, prostate tumor model, CWR-22, and just as effective as anti-androgen chemotherapy. In a schedule dependency study, increasing the interval of time between oral administrations resulted in greater cumulative dose tolerance and improved therapeutic outcome. Oral BMS-275183 was evaluated as a combination therapy in conjunction with i.v. paclitaxel. Therapeutic advantages were evident for tumor-bearing mice that received the oral taxane either after induction chemotherapy or between courses of such treatment. BMS-275183 is currently in Phase I clinical trials at multiple sites.

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