Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668

摘要: Purpose: To determine the effects of small molecule inhibitors vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on phosphorylation in tumor xenografts paired biopsies obtained three clinical trials patients with advanced solid malignancies. Experimental Design: The dose-dependent SU6668 angiogenesis were investigated orthotopic L3.6pl pancreatic tumors. Excisional or 18G core from before after therapy SU5416 SU6668. Laser scanning cytometry–mediated analysis was used to quantify levels phosphorylated total VEGFRs platelet-derived receptors (PDGFR), microvessel densities, vessel sizes, cell apoptosis. Results: Significant inhibition density increased apoptosis observed at maximum tolerated dose (100 mg/kg) xenografts. At 6 hours post therapy, reduced VEGFR PDGFR tumors by 50% 92%, respectively, but rebounded beyond baselines 24 hours. Levels VEGFR-2 also decreased significantly (≈50%) 1 primary human treated SU6668, these not associated A significant increase one exposed an size, changes occurred without death. Conclusions: displayed biological activity However, neither drug produced marked patient