Clinical approaches toward tumor angiogenesis: past, present and future.

Angiogenesis is a complex process which is critical for the growth, invasion, and metastasis of tumors. In the past ten years numerous new agents have been developed as angiogenesis inhibitors. Angiogenesis inhibitors can be classified by their targeted area of the angiogenic process; (1) VEGF and its receptors VEGFR (e.g. Bevacizumab); (2) tyrosine kinases within endothelial cells (Sunitinib); (3) proliferation of endothelial cells (Endostatin); (4) MMPs (Marimastat); (5) intercellular interactions via integrins (Cilengitide) and (6) combinations of the above mechanisms (Thalidomide). Some showed anti-tumor effects with objective responses and stable disease, and some disappeared from clinical use due to unexpected side effects or insufficient efficacies. Further investigations of combined therapies including angiogenesis inhibitors will shed light on the treatment of advanced and metastasized malignancies.