Anti-angiogenic therapy against gastrointestinal tract cancers

Gastrointestinal tract cancers constitute a group of highest morbidity both in and outside Japan, and the prognosis still remains unfavorable when the disease has progressed to the unresectable stage. Since the late 1990s, a novel category of anti-cancer drugs, 'molecular-targeted drugs', has become available, and angiogenesis has been considered as one of the most important molecular targets for antitumor therapy since it is essential for tumor growth. Anti-angiogenic therapy inhibits tumor angiogenesis and promotes apoptosis of existing tumor blood vessels, thereby intercepting the supply of oxygen and nutrition essential for tumor growth and metastasis. It was also suggested that anti-angiogenic therapy effectively normalizes abnormal vascular permeability, and thereby decreases the interstitial pressure, which may improve delivery of concomitantly used chemotherapeutic agents to tumor cells. Vascular endothelial growth factor (VEGF) acts as one of the most potent stimulating agents of angiogenesis, and several strategies targeting the VEGF signaling pathway have been developed, including anti-VEGF antibodies, soluble receptors binding directly to VEGF ligand, anti-VEGF receptor (VEGFR) antibodies and VEGFR tyrosine kinase inhibitors. The breakthrough in the clinical development of anti-angiogenic therapy against colorectal cancer came in 2003 with a large prospective, randomized clinical trial of bevacizumab, a monoclonal antibody directed against VEGF. Anti-angiogenic therapy has introduced a highly effective, completely new mode of action in this area and is the new standard of care in advanced colorectal cancer, while still being tested in gastric cancer due to its convincing clinical benefit and its tolerability and combinability with multiple chemotherapeutic agents.