The Angiogenesis Inhibitor SU5416 Has Long-lasting Effects on Vascular Endothelial Growth Factor Receptor Phosphorylation and Function

SU5416, a selective inhibitor of the tyrosine kinase activity of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR, is currently in Phase III clinical trials for the treatment of advanced malignancies. In cellular assays, SU5416 inhibits the VEGF-dependent mitogenic/proliferative resp...

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Published in:	Clinical cancer research Vol. 6; no. 12; pp. 4848 - 4858
Main Authors:	MENDEL, Dirk B, SCHRECK, Randall E, WEST, David C, GUANGMIN LI, STRAWN, Laurie M, TANCIONGCO, Sheila S, VASILE, Stefan, SHAWVER, Laura K, CHERRINGTON, Julie M
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-12-2000
Subjects:	3T3 Cells Angiogenesis Inhibitors - pharmacokinetics Animals Antineoplastic agents Biological and medical sciences Cell Division - drug effects Cell Membrane - metabolism Cell Separation Cells, Cultured Chemotherapy Culture Media, Serum-Free - metabolism Dose-Response Relationship, Drug Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Epitopes Female Flow Cytometry Humans Indoles - pharmacokinetics Kinetics Medical sciences Mice Mice, Nude Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases - metabolism Neoplasm Transplantation Neovascularization, Pathologic Pharmacology. Drug treatments Phosphorylation - drug effects Protein Binding - drug effects Protein-Tyrosine Kinases - metabolism Pyrroles - pharmacokinetics Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - biosynthesis Receptor Protein-Tyrosine Kinases - metabolism Receptors, Growth Factor - antagonists & inhibitors Receptors, Growth Factor - biosynthesis Receptors, Growth Factor - metabolism Receptors, Vascular Endothelial Growth Factor Signal Transduction - drug effects Time Factors Tumor Cells, Cultured Umbilical Cord - cytology Umbilical Cord - drug effects Antineoplastic agent Cell proliferation Phosphorylation Heterograft Angiogenesis Signal transduction Established cell line Neovascularization Mechanism of action Antiangiogenic agent Protein-tyrosine kinase Human Enzyme Transferases Rodentia Enzyme inhibitor Malignant tumor In vitro Long term Biological activity Vertebrata Chemotherapy Growth factor receptor Mammalia Vascular endothelium growth factor Treatment Mouse Animal
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Summary:	SU5416, a selective inhibitor of the tyrosine kinase activity of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR, is currently in Phase III clinical trials for the treatment of advanced malignancies. In cellular assays, SU5416 inhibits the VEGF-dependent mitogenic/proliferative response of human umbilical vein endothelial cells (HUVECs). In tumor xenograft models, SU5416 inhibits the growth of tumors from a variety of origins by inhibiting tumor angiogenesis. In three different human tumor xenograft models, infrequent (once or twice a week) administration of SU5416 is efficacious despite the fact that it has a short plasma half-life (30 min), which suggests that SU5416 has long-lasting inhibitory activity in vivo . The goal of the present study was to determine the basis for the prolonged activity of SU5416. The results indicate that a short (3 h) exposure to 5 μ m SU5416 (to mimic plasma levels of the compound as measured in patients who were receiving SU5416 therapy) produced long-lasting (at least 72 h) inhibition of the VEGF-dependent proliferation of HUVECs in culture, which indicate that SU5416 has long-lasting inhibitory activity in vitro as well as in vivo . SU5416 treatment of HUVECs did not affect surface expression of Flk-1/KDR or the affinity of the receptor for VEGF. Instead, the durability of the in vitro activity of SU5416 was shown to be attributable to its long-lasting ability to specifically inhibit VEGF-dependent phosphorylation of Flk-1/KDR and subsequent downstream signaling, although SU5416 is not an irreversible inhibitor of Flk-1/KDR tyrosine kinase activity. The long-lasting inhibition of cellular responses to VEGF was attributable to the accumulation of SU5416 in cells, as shown using radiolabeled compound, such that inhibitory cellular concentrations of SU5416 are maintained long after the removal of the compound from the medium. The long-lasting inhibitory activity of SU5416 in vitro is consistent with the finding that SU5416 has demonstrated evidence of biological activity in clinical studies when administered twice a week despite a short plasma half-life.
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ISSN:	1078-0432 1557-3265