Clinical studies of angiogenesis inhibitors: the University of Texas MD Anderson Center Trial of Human Endostatin.
Most solid-tumor malignancies remain incurable. Novel agents that target and counteract biologic mechanisms are now being developed. It is hoped that these drugs will allow for more effective, less toxic cancer treatments and long-term maintenance approaches. One important class of agents functions by an anti-angiogenic mechanism, targeting the blood vessel supply of the tumor and inhibiting tumor growth. Several principles are common to these new agents. First, because many of these agents are growth-inhibiting molecules that work exclusively against the tumor vasculature, single agents will have little effect on tumor size in advanced disease. Second, because these agents are relatively non-toxic, they are unlikely to induce the side effects associated with chemotherapy. Because endothelial cells seldom divide in a human host, anti-angiogenic compounds are expected to produce little toxicity. Third, most of these agents work synergistically with chemotherapy and/or radiotherapy. Ironically, combining these relatively non-toxic agents with chemotherapy often produces the toxicities usually associated with anticancer regimens. Anti-angiogenic agents might ultimately be studied in minimal disease. Clinical studies must demonstrate that these agents affect tumor vasculature, and phase I trials should include built-in surrogate endpoints. This article defines the general principles of anti-angiogenic drug action and explains how these principles have been used to design a phase I trial of human endostatin.
Herbst, RS; Lee, AT; Tran, HT; Abbruzzese, JL
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