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Conrad Notes
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TUMOR ANTIANGIOGENESIS: COMBRESTATIN A-4 (COA-4)
D. Chaplin, MD, Mount Vernon Hospital, Northwood, UK, found COA-4 destroyed endothelial cells in breast and colon cancer. At low concentrations, this drug damages endothelial cells. COA-4 destroys cells by binding to endothelial tubulin. Preclinical safety and efficacy studies support its evaluation in breast cancer patients. (See related reports of Dirix and Vermeulen in this issue of Conrad Notes.)

Colchicine and podophyllotoxin Both are old drugs which selectively damage tumor blood vessels; however, this effect occurs only at maximally tolerated doses. The lack of acceptable safety discourages clinical use of either medication as a vascular targeting agent.
Tissue culture results with COA-4 Low concentrations of COA-4 kill endothelial but not breast cancer cells. A 2-hour exposure, enhanced by 1% oxygen, also leads to a change in endothelial cell shape. The altered morphology may help produce a decrease in blood flow through tumor vessels which results in a lower supply of nutrients.
Evaluation in experimental breast cancer Chaplin screens potential vascular targeting agents by using implanted breast tumor cells. Inguinal deposition into rats induces growth of a tumor having a single artery and vein. Fourteen days later, 200 mM of COA-4 is injected directly into the tumor artery. Within 5 minutes, blood vessel constriction occurs as seen by the increased pressure needed to force fluid into the tumor artery. Direct femoral artery injection of COA-4 failed to produce an increase in perfusion resistance.
Skid mouse breast cancer Injected COA-4 at one tenth the minimum lethal dose (MLD) caused hemorrhagic necrosis in the central region of this tumor. The outside rim remained viable and grew rapidly inward. Multiple doses, supplemented by irradiation for 2 weeks, led to a significant delay in tumor growth and a 50% cure rate at 6 months. The data prompted Chaplin to recommend initial clinical evaluation of COA-4 in human breast cancer.

Eugene A. Conrad

Presented at The European Cancer Conference (ECCO 9), September 14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
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