CLINICAL DEVELOPMENT OF ANTICANCER AGENTS FROM NATURAL-PRODUCTS

Recent years have seen the introduction into clinical trials of new cl asses of chemotherapeutic agents which are derived from natural source s and have novel mechanisms of action. Examples of some of these newer classes of agents are presented here to illustrate both the opportuni ties they represent with respect to cancer treatment applications and the challenges which they represent from the clinical development pers pective. Cumulatively the problems encountered with the development of the agents described are representative of the spectrum of issues enc ountered in the development of natural products, ranging from initial characterization and purification through the difficulties encountered in obtaining sufficient quantities of material for preclinical studie s and then ultimately for clinical trials. Since these agents have uni que mechanisms of action and are often exquisitely dose- and schedule- dependent in preclinical studies, they represent significant complexit ies with respect to determining the optimal regimen of administration clinically. The particular agents chosen for description here represen t the spectrum of natural source-derived materials as well as mechanis ms of action. The taxanes are derived from tree sources and interfere with the mitotic spindle apparatus; the camptothecins, while also deri ved from trees, appear to exert their activity through interactions wi th topoisomerase I. Bryostatin, derived from a marine animal, has powe rful effects on protein kinase C (PKC), and therefore affects signal t ransduction pathways within cells. Fumagillin analogs appear to exhibi t their important antitumor activity not through a direct effect on ca ncer cells but rather through effects on the tumor neovasculature. Tak en as a whole, the spectrum of agents and activities described here co nfirms the continued importance of natural products in current antican cer agent development and reflects the complexities involved in this a rea of clinical research.