Clinical trials of antiangiogenic agents.

Complete inhibition of angiogenesis should be well tolerated in most adults because under physiologic conditions angiogenesis is required only for wound healing and reproduction. However, angiogenesis is required for malignant solid tumor growth beyond 1 to 2 cubic millimeters, and microvessel counts in tumor specimens have been correlated with prognosis in patients with malignancies of the breast, prostate, and central nervous system. Antiangiogenic agents that bind to heparin-binding growth factors, inactivate matrix metalloproteinases, or inhibit endothelial cell proliferation are currently being tested as single agents in clinical trials. Recombinant proteins such as interferon alfa and platelet factor 4 may also have antiangiogenic activity through mechanisms that are not yet completely defined. Because they act through diverse mechanisms of action, antiangiogenic agents may achieve maximum biologic effect when administered together. These agents are particularly attractive in the surgical adjuvant setting because the risk for development of drug resistance and induction of second malignancies is low.