In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors Determination of a Pharmacokinetic/Pharmacodynamic Relationship

摘要: One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been identification biologically active dose rather than maximum tolerated dose. The goal present study was identify pharmacokinetic/pharmacodynamic relationship preclinical models that could be used help guide selection SU11248, novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well antiangiogenic activity via targeting vascular endothelial growth factor (VEGF), platelet-derived (PDGF), KIT, FLT3 kinases, pharmacological agent these studies. In mouse xenograft models, SU11248 exhibited broad potent causing regression, arrest, or substantially reduced various established xenografts derived from human rat tumor cell lines. To predict target exposure required achieve we directly measured phosphorylation before after treatment correlated this plasma levels. modulation studies vivo , selectively inhibited Flk-1/KDR (VEGF 2) PDGF β (in time- dose-dependent manner) when concentrations reached exceeded 50–100 ng/ml. Similar results were obtained functional assay VEGF-induced permeability . Constant inhibition VEGFR2 not for efficacy; at highly efficacious doses, sustained 12 h 24-h dosing interval. aided design, selection, evaluation regimens being tested trials.