Inhibitors of tumor angiogenesis
Harris AL., Generali DG.
This chapter discusses the inhibitors of tumor angiogenesis. Angiogenesis is a complex process involving a plethora of activating and inhibiting factors. Most of the currently available proteins and peptides with antiangiogenic activities have greatly contributed to the understanding and modulation of the molecular mechanism of tumor angiogenesis. Several proteins (antibodies) and peptides have entered clinical testing as anti-angiogenic drugs, and some of them are now approved for clinical use (e.g. bevacizumab). In addition, targeted drugs that have been developed for non-angiogenesis related therapies have been found to affect the tumor vasculature (e.g. Glivec). The identification of novel target molecules, the development of new drugs, and clinical testing will tell us whether peptides and antibodies, or small-molecule inhibitors, will become the leading anti-angiogenic compounds in clinical practice. It is increasingly likely that cancer therapy, with few exceptions, will need to be combinatorial. It seems logical to target multiple pathways simultaneously. For example, early primary breast cancer can express up to six pro-angiogenic proteins. Therefore, it is likely that residual tumors in a patient could express multiple angiogenic factors, and that such tumors could become refractory to an angiogenesis inhibitor that blocks a single angiogenic factor. To prevent such a potential refractory state, combinations of indirect angiogenesis inhibitors, or multi-targeted agents such as sorafenib or ZD6474 with bevacizumab, able to inhibit as many pathways as possible without losing their specificity against pathological angiogenesis, will be crucial for blocking tumor angiogenesis completely. © 2008 Elsevier Inc. All rights reserved.