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The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis

Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2008-06, Vol.68 (12), p.4754-4762
Main Authors: Heckman, Caroline A, Holopainen, Tanja, Wirzenius, Maria, Keskitalo, Salla, Jeltsch, Michael, Ylä-Herttuala, Seppo, Wedge, Stephen R, Jürgensmeier, Juliane M, Alitalo, Kari
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Holopainen, Tanja
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description Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of
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Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. 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subjects Adenoviridae - genetics
Angiogenesis Inhibitors - pharmacology
Animals
Blotting, Western
Cell Membrane Permeability - drug effects
Cell Movement - drug effects
Cell Proliferation - drug effects
Cell Survival - drug effects
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Humans
Immunoprecipitation
Lymphangiogenesis - drug effects
Lymphangiogenesis - physiology
Male
Mice
Mice, Nude
Neovascularization, Pathologic - prevention & control
Phosphorylation - drug effects
Quinazolines - pharmacology
Signal Transduction
Skin - cytology
Skin - drug effects
Skin - metabolism
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor C - genetics
Vascular Endothelial Growth Factor C - metabolism
Vascular Endothelial Growth Factor D - genetics
Vascular Endothelial Growth Factor D - metabolism
Vascular Endothelial Growth Factor Receptor-2 - genetics
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vascular Endothelial Growth Factor Receptor-3 - genetics
Vascular Endothelial Growth Factor Receptor-3 - metabolism
title The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis
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