DOCETAXEL (TAXOTERE(R)) - A REVIEW OF PRECLINICAL AND CLINICAL-EXPERIENCE .1. PRECLINICAL EXPERIENCE

Docetaxel is a taxoid which is currently in phase II/III clinical tria ls in Europe, the US and Japan. It was found to promote tubulin assemb ly in microtubules and to inhibit their depolymerization. In vitro, th e docetaxel concentrations required to reduce murine and human cell su rvival by 50% ranged from 4 to 35 ng/ml and the cytotoxic effects were greater on proliferating than on non-proliferating cells. It was also found to be cytotoxic on fresh human tumor biopsies. In vivo, the dru g was found to be schedule independent. A total of 13/14 murine transp lantable tumors were found very sensitive to i.v. docetaxel and comple te regressions of advanced stage tumors were obtained. Activity was al so observed in 15/16 human tumor xenografts in nude mice at an advance d stage. In combination studies, synergism was observed in vivo with 5 -fluorouracil, cyclophosphamide and etoposide. Pharmacokinetic evaluat ion revealed linear pharmacokinetics in tumor-bearing mice. There was a good tumor retention with a 22 h elimination half-life. Plasma prote in binding ranged from 76 to 89%. preclinical toxicology evaluation of docetaxel included single-dose toxicity in rats, mice and dogs, B-day toxicity in mice and dogs, intermittent-dose toxicity in rats, dogs a nd monkeys, genetic and reproductive toxicity, as well as investigatio n of the irritation and sensitization potential. The principal toxicit ies were hematopoietic (all species), gastrointestinal (dog, monkey) a nd neuromotor (mice). Dogs appeared to be the most sensitive species. The clinical entry dose of 5 mg/m(2) was based on one-third of the 'to xic dose low' in dogs (15 mg/m(2)).