Cell-targeted cytotoxics: a new generation of cytotoxic agents for cancer treatment

Abstract

The therapeutic arsenal for the treatment of cancers has been considerably revised over the past 15 years, with the continuous launch of molecularly-targeted drugs, essentially kinases inhibitors and monoclonal antibodies. In the mean time, different conventional cytotoxic agents derived from natural products have also been developed successfully, providing novel advances for certain forms of advanced cancers. But most drug development are now oriented toward the design of cancer-cell targeted molecules, in particular products incorporating a tumor cell-delivery vector or a penetrating moiety. This emerging class of anti-cancer agents is discussed here with two specific drug candidates currently in clinical development. The first example is the tubulin-binding Vinca-alkaloid vintafolide, targeted to cancer cell over-expressing the folate receptor and currently in phase 3 for the treatment of patients with platinum-resistant ovarian cancer. The second example is that of the hybrid compound F14512 composed of an epipodophyllotoxin core coupled to a spermine side in order to promote the uptake of the drug by cells over-expressing the polyamine transport system. The topoisomerase II poison F14512 is currently in phase 1 for the treatment of acute myeloid leukemia. These two promising drugs, both derived from plant natural products and developed with a specific biomarker, are the leaders in the class of cell-targeted cytotoxic agents that should offer not only gains in efficacy, but also in safety and tolerability in the treatment of patients with cancer. Different strategies are proposed to guide the delivery of cytotoxic agents to cancer cells.