Stem Cells, Vol 12, 30-43, Copyright © 1994 by AlphaMed Press
Clinical development of anticancer agents from natural products
DR Parkinson, SG Arbuck, T Moore, JM Pluda and MC Christian
Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892.
Recent years have seen the introduction into clinical trials of new classes
of chemotherapeutic agents which are derived from natural sources and have
novel mechanisms of action. Examples of some of these newer classes of
agents are presented here to illustrate both the opportunities they
represent with respect to cancer treatment applications and the challenges
which they represent from the clinical development perspective.
Cumulatively the problems encountered with the development of the agents
described are representative of the spectrum of issues encountered in the
development of natural products, ranging from initial characterization and
purification through the difficulties encountered in obtaining sufficient
quantities of material for preclinical studies and then ultimately for
clinical trials. Since these agents have unique mechanisms of action and
are often exquisitely dose- and schedule-dependent in pre-clinical studies,
they represent significant complexities with respect to determining the
optimal regimen of administration clinically. The particular agents chosen
for description here represent the spectrum of natural source-derived
materials as well as mechanisms of action. The taxanes are derived from
tree sources and interfere with the mitotic spindle apparatus; the
camptothecins, while also derived from trees, appear to exert their
activity through interactions with topoisomerase I. Bryostatin, derived
from a marine animal, has powerful effects on protein kinase C (PKC), and
therefore affects signal transduction pathways within cells. Fumagillin
analogs appear to exhibit their important antitumor activity not through a
direct effect on cancer cells but rather through effects on the tumor
neovasculature. Taken as a whole, the spectrum of agents and activities
described here confirms the continued importance of natural products in
current anticancer agent development and reflects the complexities involved
in this area of clinical research.
