Preclinical pharmacology of BMS-275183, an orally active taxane.
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.
Rose
W C
WC
Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, New Jersey 08543, USA. rosew@bms.com
Long
B H
BH
Fairchild
C R
CR
Lee
F Y
FY
Kadow
J F
JF
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C437188:BMS-275183; D001952:Bridged-Ring Compounds; D017239:Paclitaxel