Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts.

Abstract

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation.

• Authors: Neil R Smith, Neil H James, Ian Oakley, Anna Wainwright, Clive Copley, Jane Kendrew, Lynsey M Womersley, Juliane M Jürgensmeier, Stephen R Wedge, Simon T Barry
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 8 Pg. 2198-208 (Aug 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17699717 (Publication Type: Journal Article)

Chemical References

• Antibodies, Neoplasm
• Antibodies, Phospho-Specific
• Antineoplastic Agents
• Quinazolines
• Vascular Endothelial Growth Factor A
• Phosphotyrosine
• Vascular Endothelial Growth Factor Receptor-2
• cediranib

Topics

• Animals
• Antibodies, Neoplasm
• Antibodies, Phospho-Specific
• Antineoplastic Agents (pharmacology)
• Female
• Humans
• Lung Neoplasms (blood supply, pathology)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (drug therapy)
• Phosphorylation (drug effects)
• Phosphotyrosine (metabolism)
• Quinazolines (pharmacology)
• Reproducibility of Results
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays