Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions.

Abstract

Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For other agents, such as vatalanib, contrasting outcomes in metastatic colorectal cancer patients have been reported: the final results of these trials are expected in 2006. However, several key questions remain to be addressed, regarding the choice of an adequate dose or schedule, the presence of "off-target" effects, the safety of long-term administration, and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents.

• Authors: Alessandro Morabito, Ermelinda De Maio, Massimo Di Maio, Nicola Normanno, Francesco Perrone
• Journal: The oncologist (Oncologist) 2006 Jul-Aug Vol. 11 Issue 7 Pg. 753-64 ISSN: 1083-7159 [Print] England
• PMID: 16880234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Angiogenesis Inhibitors
• Piperidines
• Protein Kinase Inhibitors
• Quinazolines
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Protein-Tyrosine Kinases
• Receptors, Vascular Endothelial Growth Factor
• vandetanib

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Clinical Trials as Topic
• Humans
• Neoplasms (drug therapy)
• Piperidines (therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinazolines (therapeutic use)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Vascular Endothelial Growth Factor A (metabolism)