The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function.

摘要: SU5416, a selective inhibitor of the tyrosine kinase activity the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR, is currently in Phase III clinical trials for treatment advanced malignancies. In cellular assays, SU5416 inhibits VEGF-dependent mitogenic/proliferative response human umbilical vein endothelial cells (HUVECs). tumor xenograft models, growth of tumors from variety origins by inhibiting angiogenesis. In three different infrequent (once or twice week) administration is efficacious despite fact that it has short plasma half-life (30 min), which suggests that SU5416 long-lasting inhibitory vivo . The goal present study was to determine basis prolonged activity SU5416. The results indicate that (3 h) exposure to 5 μm (to mimic levels compound as measured patients who were receiving therapy) produced long-lasting (at least 72 inhibition VEGF-dependent proliferation HUVECs culture, has long-lasting vitro as well as did not affect surface expression Flk-1/KDR or affinity the receptor VEGF. Instead, durability in vitro shown be attributable to its ability specifically inhibit VEGF-dependent phosphorylation and subsequent downstream signaling, although not an irreversible tyrosine kinase activity. responses to VEGF accumulation cells, shown using radiolabeled compound, such cellular concentrations are maintained long after removal the compound medium. of SU5416 consistent with finding demonstrated evidence biological clinical studies when administered twice week plasma half-life.