The Food and Drug Administration has recently approved sorafenib and sunitinib, two oral multitargeted tyrosine kinase inhibitors, for the treatment of advanced renal cell carcinoma (RCC). Because of the central role of vascular endothelial growth factor (VEGF) in this disease and the activity of VEGF-targeted agents, RCC serves as a unique arena for the evaluation of antiangiogenic agents. In clear cell RCC, mutation or deletion of the von Hippel-Lindau gene is the defining somatic genetic event (1). This results in unopposed activity of the hypoxia-inducible factor signaling complex that regulates the transcription of a number of proangiogenic growth factors, of which VEGF is the best studied. Supporting the essential role of VEGF in the malignant phenotype in RCC, a monoclonal antibody targeted to VEGF exerts its greatest single-agent activity in this disease (2). Sorafenib and sunitinib antagonize VEGF receptor (VEGFR) tyrosine kinases as well as numerous...

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