Chapter 15. Inhibitors of Angiogenesis

Abstract

Publisher Summary This chapter discusses the recent progress in identifying the key cellular and molecular features of angiogenesis and illustrates the recent novel compounds that have potential clinical utility. Among the in vivo assays, the chicken chorioallantoic membrane (CAM) assay and intradermal assays involve angiogenic responses on a background of existing vasculature. Angiogenic growth factors stimulate endothelial cell migration, and, therefore, the ability of compounds to prevent motility is often examined in chemokinesis and/or chemotaxis assays. Interferon-α deserves special mention because it is the first clinically successful inhibitor of angiogenesis. Early work has demonstrated that interferon inhibits the in vitro motility of capillary endothelial cells and reduces the in vivo angiogenesis. It is observed that certain tissues are avascular led investigators to postulate that these tissues contain endogenous inhibitors of angiogenesis. Cartilage-derived inhibitor (CDI) inhibits endothelial cell proliferation and migration in vitro and blocks angiogenesis in the CAM assay. The importance of extracellular matrix molecules in controlling capillary blood vessel morphogenesis has recently been reviewed. Two synthetic peptides based on amino acid sequences found in active domains of laminin blocked the formation of capillary sprouts in vitro . Although the ribonuclease activity of angiogenin is dramatically less than that of RNases, human placental ribonuclease inhibitor (PRI) binds to angiogenin with high avidity. Platelet factor 4 (PF4) has been studied as an angiogenesis inhibitor because it binds to heparin. Heparin also enhances the angiogenic activity present in tumor extracts. The identification of a naturally secreted antibiotic of Aspergillus furnigatus , fumagillin, as an angiogenesis inhibitor provides the impetus for the discovery of novel small molecular weight inhibitors of neovascularization. Inhibitors of collagen biosynthesis and processing are the inhibitors of angiogenesis. Numerous small molecular weight compounds have been also reported to inhibit angiogenesis in CAM or cornea assays.