Preclinical pharmacology of BMS-275183, an orally active taxane

Clin Cancer Res. 2001 Jul;7(7):2016-21.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bridged-Ring Compounds / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred DBA
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control
  • Paclitaxel / pharmacology
  • Rats
  • Rats, Nude
  • Time Factors
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BMS-275183
  • Bridged-Ring Compounds
  • Paclitaxel