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.