Vascular endothelial growth factor and its inhibitors.

Originally identified for its ability to induce vascular permeability and stimulate endothelial cell growth, vascular endothelial growth factor (VEGF) is now recognized as a key factor required for growth of tumors and is involved in many other diseases, such as diabetes, arthritis, atherosclerosis and ischemic heart disease. In addition, recent studies show that VEGF is involved in stem cell recruitment and mobilization. A new role of VEGF has been postulated in enhancing the production and release into the circulation of endothelial progenitor cells derived from the bone marrow. These circulating endothelial cells may be targeted to angiogenic sites where they are being incorporated in new vessels. We provide an overview of the biological role of VEGF and summarize the different approaches that are under development to inhibit VEGF activity in the clinic, particularly antiangiogenic cancer treatment. Thus far, more than five inhibitors of the VEGF pathway have entered clinical phase I-III trials. Of these, bevacizumab, an antibody against VEGF, was shown to prolong survival in a phase III trial in renal cell cancer. Although very preliminary, a phase I trial found tumor regressions that were caused by an oral VEGF receptor tyrosine kinase inhibitor, SU11248. Taken together, these data seem very promising for the development of long-term nontoxic treatments against cancer.