Recent concepts of antiangiogenic therapy.

In 2004, a randomized, controlled phase III clinical trial showed that the addition of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, to conventional chemotherapy prolonged the survival of patients with metastatic colorectal cancer. A number of clinical trials are presently underway to test the utility of several angiogenic inhibitors against a variety of malignancies. The original concept of antiangiogenic therapy was the inhibition of outgrowth of new blood vessels; however, it soon became evident that bevacizumab could affect the vasculature through various mechanisms. Recent studies have shown that antiangiogenic agents can normalize the tumor vasculature and prevent the recruitment of endothelial progenitor cells from the bone marrow. Some preclinical studies have also shown that antiangiogenic agents prevent metastasis by modulating the premetastatic niche. Understanding these detailed mechanisms provides the rationale for combination therapy using antiangiogenic agents and cytotoxic chemotherapy, and will lead to more effective treatment strategies. In this review, we summarize the present understanding of the mechanisms of action of antiangiogenic agents and discuss the future prospects of antiangiogenic therapies.