James Samanen, Zdenka Jonak, David Rieman and Tian-Li Yue Pages 545 - 584 ( 40 )
During early investigations into the biology associated with the platelet integrin αllbβ3, monoclonal antibodies to αllbβ3 indicated that an αllbβ3-like integrin was expressed on endothelial cells, smooth muscle cells and on a variety of cancer cell lines. That integrin became known as the vitronectin receptor. It was shown to contain the same β3 subunit as αllbβ3, but it contained a different alpha subunit, named αv. Instead of a large family of β3 integrins, a large family of av integrins was discovered. To date, the family includes αvβI, αvβ3, αvβ5, αvβ6 and αvβ8. Two members of the family, αvβ3 and αvβ5, have received the most attention, showing potential in therapeutic targets as diverse as osteoporosis, restenosis and angiogenesis. This paper focuses on the potential vascular indications for αv antagonists. It reviews the role of αvβ3 and αvβ5 as smooth muscle cell and endothelial cell adhesion receptors, as well as their capacity to mediate cell spreading and migration as signaling receptors. The current evidence for the role of αvβ3 and αvβ5 in restenosis and angiogenesis is reviewed. Endothelial cells, smooth muscle cells, and macrophages (mΦ) express either integrin, depending upon the cytokine that drives the migratory phenotype. Accessory membrane-bound molecules and matrix-degrading proteinases, as well as subcellular second messengers are reviewed. A model for the involvement of Integrin Associated Protein (IAP), and its ligation by thrombospondin is also proposed. A number of αv antagonists that inhibit cell adhesion to αvβ3 and αvβ5 have succeeded in proof of concept experiments in animal disease models. Nonpeptide av antagonists with high selectivity and adequate oral bioavailability have also been discovered. Thus, the field of αv antagonists is poised to move into clinical development in the areas of restenosis, cancer, and ocular angiogenesis. Other areas that could blossom with potential for αv antagonists include rheumatoid arthritis and atherosclerosis.