Therapies directed at vascular endothelial growth factor.
The inhibition of angiogenesis through vascular endothelial growth factor (VEGF) receptor targeting is a strategy that is relatively tumour selective. The high selectivity achieved with neutralising antibodies, soluble receptors and ribozymes reduces the risk of adverse reactions not related to VEGF inhibition itself. Small-molecule, orally-active protein kinase inhibitors provide an attractive alternative for chronic therapy, although specifically targeting a small subset of protein kinases from the approximately 550 expressed in mammalian cells is a challenge. Current efforts have resulted in promising clinical data for several synthetic VEGF receptor kinase inhibitors, of which PTK787/ZK222584 and ZD6474 are proceeding into large size clinical trials. It seems likely that blockers of the VEGF signalling pathway will be unsuitable for monotherapy, and that their role will be as an adjunct to additional antiangiogenic agents together with directly-acting antitumour agents or radiation therapy. Caution is needed with combinations of anti-VEGF therapies and cytotoxic agents, as coadministration of cytotoxic agents with either the kinase inhibitor SU5416 or the VEGF antibody avastin appears to be associated with bleeding and thrombotic adverse events.
Manley
Paul W
PW
Novartis Pharma Ltd, CH-4057 Basel, Switzerland.
Martiny-Baron
Georg
G
Schlaeppi
Jean-Marc
JM
Wood
Jeanette M
JM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000209:etiology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D015316:Genetic Therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D009362:Neoplasm Metastasis; D018919:Neovascularization, Physiologic; D016337:RNA, Catalytic / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016337:RNA, Catalytic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor