Preclinical pharmacology of docetaxel.
Docetaxel is a taxoid cytotoxic agent which promotes tubulin assembly into microtubles and inhibits their depolymerisation. In vitro, docetaxel reduces murine and human tumour cell survival by 50% at concentrations of 4-35 ng/ml, with a greater cytotoxic effect on proliferating than on non-proliferating cells. In vivo, docetaxel is schedule-independent. Over 80% of murine transplantable tumours were found to be very docetaxel sensitive, with complete regression of advanced stage tumours. Activity was also observed in > 90% of advanced stage human tumour xenografts in mice. In combination therapy studies, synergism with 5-fluorouracil, cyclophosphamide and etoposide was observed in vivo. Docetaxel exhibited linear pharmacokinetics and long tumour retention in tumour-bearing mice; plasma protein binding ranged from 76 to 89%. In toxicological studies in mice and dogs, docetaxel produced haematological, gastrointestinal and neuromotor toxicity. The dog was found to be the most sensitive species to the toxic effects of docetaxel.
Bissery
M C
MC
Rhône-Poulenc Rorer S.A., Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine Cedex, France.
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel