Tumor Suppression By Angiogenesis Disruption

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TUMOR SUPPRESSION BY ANGIOGENESIS DISRUPTION

L.Y. Dirix, MD, University of Antwerp, Belgium, discussed the suppression of tumor growth and metastases by disrupting blood vessels. Angiogenesis inhibitors and vascular targeting agents show promise in treating cancer and other diseases. (See the related reports of Chaplin and Vermeulen in this issue of Conrad Notes).
The role of angiogenesis in disease	Folkman provided a comprehensive review of blood vessel formation in cancer and other diseases (Nature Med 1995;1:27-31). Excessive angiogenesis also occurs in rheumatoid arthritis, psoriasis, duodenal ulcers, and hemangioma. Folkman described several key chemicals and activities in angiogenesis: vascular endothelial growth factor (VEGF) is the principal mediator for blood vessel formation in the primary tumor. VEGF disappears from the circulation upon removal of the primary tumor and intense angiogenesis follows in the metastases. angiostatin, a 38 kD protein of uncertain origin, inhibits endothelial cell proliferation. p53 tumor suppressor gene normally controls the angiogenesis inhibitor, thrombospondin.
Modulating angiogenesis by treatment	Two type of agents counteract angiogenesis. One group inhibits the process and the other targets blood vessels. The blockers interfere with endothelial cells in the beginning by degrading the basal membrane. Later, the inhibitors disrupt cell migration, proliferation, and tubule formation. Vascular-targeting chemicals selectively destroy tumor blood vessels. The resultant decrease in tumor metabolism leads to shrinkage and necrosis.
Inhibiting the angiogenesis process	Phase II clinical studies are in progress with the following angiogenesis inhibitors: platelet factor 4 injected intravenously to treat lymphoma TNP-470, a fumagillin byproduct, also inhibits tumor growth thalidomide, a teratogen and sedative, to treat prostate cancer
Vascular targetting treatments	The agent CM 101 binds to tumor endothelium, activates complement, and causes selective tumor vessel damage. These actions result in rapid tumor necrosis. Other chemicals in this group are combrestatin A-4 (COA-4) and its soluble prodrug. Both bind to tubulin and cause endothelial cell damage, according to Chaplin.

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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