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Research Articles

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

¹ Cancer Bioscience, AstraZeneca, and ² Antibodies and Imaging, Discovery Enabling Capabilities and Science, Alderley Park, Macclesfield, Cheshire, United Kingdom

Requests for reprints: Simon T. Barry, Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Phone: 44-1625-513350; Fax: 44-1625-513624. E-mail: Simon.T.Barry{at}astrazeneca.com

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 (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. [Mol Cancer Ther 2007;6(8):2198–208]

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Received 2/28/07; revised 5/25/07; accepted 6/27/07.

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