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.