Recent Advances in the New Generation Taxane Anticancer Agents

Abstract

Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.