[Taxotere: from yew's needles to clinical practice]

Taxotere [N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol] is a new chemical entity obtained by semisynthesis from 10-deacetylbaccatin III, a non cytotoxic precursor extracted from the needles of the European yew Taxus baccata. Taxotere retains the unique mechanism of action of taxol and inhibits the depolymerisation of microtubules into tubulin. In vitro, Taxotere is cytotoxic against murine and human tumor cells with IC50 values ranging from 4 to 35 ng/ml. Taxotere inhibits the clonogenic properties of fresh human tumor cells at clinically relevant concentrations. Taxotere is highly active in vivo against several experimental models: it is 2.7-fold more active than taxol on a log cell kill basis against B16 melanoma; ten out of the twelve models of grafted murine tumors tested respond to Taxotere; it is active with 80% complete regressions against advanced C38 colon adenocarcinoma and PO3 pancreatic ductal adenocarcinoma. Finally, Taxotere is active against several human xenografts implanted in nude mice. Safety studies were performed in dogs and mice according to NCI guidelines. Toxicological effects are observed mostly is tissues with high cell turnover (bone marrow in mice and dogs, gastrointestinal tract in dogs only) or in those where microtubules play an important role (peripheral nerves in mice only). Because of its availability, due to an efficient process using a renewable source of natural precursor, its preclinical profile (higher antitumoral activity than taxol with a comparable toxicological profile) and its unique mechanism of action, Taxotere has entered Phase I clinical trials in Europe, United States and Japan. The dose limiting toxicity is a neutropenia. Evidence of clinical activity has been noted (breast, ovarian, lung). Taxotere is now in Phase II clinical trials.