VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-A holds an exceptional position among the many molecules implicated in the regulation of blood vessel formation. During embryonic development, it controls a large number of processes, spanning from the expansion of the earliest cell progenitors of the vasculature to the control of proliferation and migration of endothelial cells, vessel remodeling, and arteriovenous specification (3). A correct level of VEGF-A protein is absolutely critical for vessel development, because a reduction of expression by half or an increase by twofold are both fatal conditions for a mouse embryo.

Given the array of critical roles for this multitalented cytokine, it would appear dangerous to expose humans to potent VEGF-pathway inhibitors. However, the ability of such inhibitors to block formation of tumor vessels and cause regression of tumors in experimental animals has provided a strong rationale for also testing VEGF-pathway blocking agents in human cancer therapy (4). Some of these agents have already shown promise in clinical trials, and one of them, the Genentech anti-VEGF-A antibody bevacizumab (Avastin), was approved by the Food and Drug Administration in 2004 for treatment of metastatic colorectal carcinoma. The fact that relatively mild and few side effects were reported from the use of Avastin in these patients came as a pleasant surprise but at the same time appeared to confirm a generally held assumption that the mature and quiescent blood vessels of normal tissues are independent of VEGF-A. There are reasons for caution, however, because regional capillary regression has been noticed in adult experimental animals as a result of inhibition of VEGF signaling. The side effects of Avastin may also have been underestimated in some of the trials conducted thus far, because treated patients are both preselected and seriously ill. In fact, Genentech recently (September 23, 2005) announced the discontinuation of a phase II clinical trial of Avastin in ovarian cancer patients because of gastrointestinal perforations in 11% of the patients (see www. medicalnewstoday. com, 29 Sep 2005).