New Vinca Alkaloids in Clinical Development

Abstract

The most successful tubulin-targeting agents in the treatment of breast cancer are the taxanes and the Vinca alkaloids. Vinorelbine, a vinca alkaloid derivative, has remarkable clinical activity in advanced breast cancer patients, and is currently used. Among the most critical limitations of Vinca alkaloids in metastatic breast cancer are their sensitivity to multidrug resistance pumps and the development of drug resistance. So, there is a need for new efficacious Vinca alkaloids agents that are associated with increased response and limited and manageable toxicity. Vinflunine is a novel microtubule inhibitor of the Vinca alkaloid class obtained by semi-synthesis using superacidic chemistry to selectively modify the catharantine moiety. In preclinical models, vinflunine is more active in vivo than the other Vinca alkaloids and resistance to vinflunine develops more slowly than that to vinorelbine. In addition, vinflunine in-vitro neurotoxicity is lower than that of vincristine and of vinorelbine. Encouraging phase II results and the favorable safety profile of vinflunine warrant further investigation of this novel agent in combination with other active agents in metastatic breast cancer. Comparative clinical trials have been initiated.