Anti-angiogenesis and RGD-containing snake venom disintegrins

Angiogenesis is the fundamental process by which new blood vessels are formed. Extensive research has shown that this event can be co-opted by tumors to ensure their growth, survival and metastasis. The study of tumor angiogenesis therefore represents a promising area of research for development of anti-cancer therapeutics. Integrins, a family of cell surface molecules, are a major target of interest as they are known to play a vital role in pathological angiogenesis. Remarkably, small disulfide-rich peptides known as disintegrins, isolated from the venoms of various snake species have been found to bind integrins with extremely high affinity and block their function. Disintegrins are capable of inhibiting several aspects of tumor cell behavior both in vitro and in vivo, including adhesion, migration, invasion, metastasis and angiogenesis. In this review, we will briefly discuss tumor angiogenesis and molecules implicated in the angiogenic process, with a special focus on the role of integrins. We will also discuss therapeutic approaches towards the treatment of tumor angiogenesis, including non-integrin-targeted agents currently in clinical trials. We will summarize the major findings from studies using disintegrins to target integrin-associated angiogenesis in cancer models. Finally, we will present results obtained in our laboratory using the novel dimeric disintegrin, contortrostatin (CN), in studies of endothelial cells and models of breast, ovarian and prostate cancer. In summary, disintegrins represent an exciting new class of molecules that can potentially be used in a clinical setting to inhibit angiogenesis and augment conventional chemotherapeutic agents in the treatment of cancer.