Mechanisms of Action of Bevacizumab as a Component of Therapy for Metastatic Colorectal Cancer

Tumor angiogenesis is a complex process that requires the coordinated activities of various effector molecules and cell types. While tumor vasculature can nourish the tumor, it is structurally and functionally abnormal, leading to elevated interstitial pressure and non-uniform tumor perfusion. The resultant hypoxia leads to the selection of more aggressive tumor cells, owing in part to an increase in the levels of the transcription factor hypoxia-inducible factor-1, which in turn leads to an increase in the expression of vascular endothelial growth factor (VEGF). The expression of VEGF is upregulated in many tumors, and the levels of this factor correlate not only with the extent of tumor angiogenesis but also with clinical prognosis. VEGF-targeted therapies, such as bevacizumab, exert their effects through a number of potential mechanisms, including (1) inhibition of new vessel growth, (2) regression of newly formed tumor vasculature, (3) alteration of vascular function and tumor blood flow ("normalization"), and (4) direct effects on tumor cells. Because of the presumed cytostatic mechanism of action of antiangiogenic agents, the efficacy of bevacizumab is most appropriately assessed through survival end points rather than the objective-response end points that have traditionally been used with cytotoxic agents. However, bevacizumab has been shown to increase the response rates with chemotherapy in almost all tumor types studied in phase III trials.