Angiogenesis inhibition in solid tumors

Angiogenesis plays a central role in a variety of physiologic and pathologic disease states. Because the growth and metastasis of malignant neoplasms require the presence of an adequate blood supply, pharmacologic inhibition of tumor-induced angiogenesis represents a promising target for antineoplastic therapy. A number of approaches to such inhibition are therefore under active investigation. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are among the best characterized of the various key elements in benign and neoplastic angiogenesis. In 1997, clinical trials were initiated to evaluate an anti-VEGF monoclonal antibody and a VEGFR-2 antagonist as therapy for patients with different types of solid tumors and hematologic neoplasms. Dose selection for these cytostatic agents requires translation from preclinical models, as these agents are likely to require chronic dosing at an optimal biological dose, rather than a maximally tolerated dose. For example, SU5416, a novel small-molecule inhibitor of VEGFR-2, administered at 145 mg/m2 intravenously twice weekly, is well tolerated and achieves the concentration levels required to inhibit endothelial cell proliferation in preclinical models. Because the mechanism of action of angiogenesis inhibitors is complementary to that of classic cytotoxic chemotherapy, preclinical models and subsequent clinical trials frequently explore combinations of these agents with cytotoxic chemotherapy, hoping to achieve additive or synergistic antitumor activity. It is hoped that the combination of angiogenesis inhibitors with cytotoxic chemotherapeutic agents will significantly improve survival and quality of life for cancer patients. As a result of favorable results from Phase 1 and 2 studies, randomized, multicenter clinical investigations of angiogenesis inhibitors are ongoing.