Clinical development of anticancer agents from natural products.
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.
Parkinson
D R
DR
Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892.
Arbuck
S G
SG
Moore
T
T
Pluda
J M
JM
Christian
M C
MC
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D054713:Bryostatins; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides; D017239:Paclitaxel / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry*; D012717:Sesquiterpenes; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D054713:Bryostatins; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D007783:Lactones; D018942:Macrolides; D012717:Sesquiterpenes; D059004:Topoisomerase I Inhibitors; C046785:bryostatin 1; C026211:fumagillin; D017239:Paclitaxel; D002166:Camptothecin