The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function
| Autor: | D B, Mendel, R E, Schreck, D C, West, G, Li, L M, Strawn, S S, Tanciongco, S, Vasile, L K, Shawver, J M, Cherrington |
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| Rok vydání: | 2001 |
| Předmět: |
Indoles
Time Factors Mice Nude Angiogenesis Inhibitors Cell Separation Culture Media Serum-Free Umbilical Cord Epitopes Mice Tumor Cells Cultured Animals Humans Pyrroles Receptors Growth Factor Phosphorylation Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Dose-Response Relationship Drug Neovascularization Pathologic Cell Membrane Receptor Protein-Tyrosine Kinases 3T3 Cells Protein-Tyrosine Kinases Flow Cytometry Kinetics Receptors Vascular Endothelial Growth Factor Female Endothelium Vascular Mitogen-Activated Protein Kinases Cell Division Neoplasm Transplantation Protein Binding Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 6(12) |
| ISSN: | 1078-0432 |
| Popis: | 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 microM 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. |
| Databáze: | OpenAIRE |
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