Integrin Antagonists and Other Low Molecular Weight Compounds as Inhibitors of Angiogenesis: New Drugs in Cancer Therapy

摘要

Angiogenesis (neovascularization). the process by which new blood capillaries are formed from an already existing blood vessel, is of fundamental importance for a number of physiological and pathological events including embryogenesis, wound healing,chronic inflammation, and malignant processes. Due to the observation that an adequate blood supply is necessary for tumor growth, Folkman postulated in the early 1970s that inhibitors of angiogenesis are of potential use in cancer therapy. Subsequent investigations revealed that not only tumor growth but also tumor metastasis depends on angiogenesis. In recent years many endogenous regulators of angiogenesis have been isolated and identified. The most important positive regulators include growth factors like basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF-), and tumor necrosis factors (TNF-α). An additional component controlling the progress of neovascularization at several stages is a protein derived from endothelialcells, SPARC (secreted protein, acidic, cysteine-rich). Its proteolytic degradation generates fragments containing the sequence Gly-His-Lys. which stimulate angiogenesis both in vitro and in vivo. The negative regulators include thrombospondin 1. angiostatin, platelet fac-tor4. and interferon α.