Drug-interaction and Formulation Aspects of Taxanes in the Treatment of Cancer

Abstract

Over forty years ago, samples of the Taxus brevifolia, the pacific yew tree, were screened by the National Cancer Institute (NCI) for anticancer activity. Screening indicated that an extract from the tree possessed activity against tumour cell lines. Paclitaxel the active compound of the extract, was isolated in its pure form in 1969. The mechanism of action was not described until 1979 when Schiff and Horwitz discovered its unique mechanism of cytotoxicity. In contrast to other mitotic agents, paclitaxel and docetaxel promoted the assembly of tubulin and stabilised the resulting microtubules. Clinical studies with paclitaxel started in 1983. At the same time French researchers produced semisynthetic derivatives of baccatin III, an extract from the needles of the European yew Taxus baccata, and modified it with a chemically synthesised side chain. Docetaxel emerged from these efforts and entered clinical trials in 1990. Drug vehicle, drug-interactions, tissue penetration and age are all factors affecting drug pharmacokinetics, and are the focus of this thesis.