[Pharmacological skills for targeting EGFR and VEGF]

Several monoclonal antibodies directed against EGFR are currently in clinical evaluation and include notably the agent cetuximab (C225). Tyrosine kinase inhibitors have chemical structures close to that of ATP and are thus ATP competitors on the tyrosine kinase site (ATP pocket) which is located in the intracellular domain of EGFR (gefitinib and erlotinib, respectively Tarceva and Iressa being the most advanced in clinical development). Well-conducted experimental studies open the way to new clinical applications with the most rewarding currently being the association between cetuximab and irinotecan. The two approaches of EGFR targeting have the same target and similar intracellular molecular impacts but they may differ under several aspects. For instance for the mechanism of action where, for monoclonal antibodies, there is a potential complement of cytotoxic activity brought by the ADCC phenomenon (antibody-directed cell cytotoxicity). One of the main current questions about the clinical use of anti-EGFR drugs is to dispose of faithful predictors for identifying tumors sensitive to this targeted treatment. The agents targeting VEGF are conceptually the same to those applied to EGFR. A major therapeutic advance brought by antiangiogenic drugs in colorectal cancer is attributable to bevacizumab. Bevacizumab is a monoclonal antibody impacting VEGF itself. A controlled clinical trial recently conducted on more than 800 advanced colorectal cancer patients concluded to a significant improvement in both response rate and global survival. This trial was comparing the combination 5FU-leucovorin-bevacizumab to 5FU-leucovorin and the advantage was in favor of the triple combination.