AEE788, a Dual Tyrosine Kinase Receptor Inhibitor, Induces Endothelial Cell Apoptosis in Human Cutaneous Squamous Cell Carcinoma Xenografts in Nude Mice

Purpose: We investigated whether concomitant blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways by AEE788, a dual inhibitor of EGFR and VEGFR tyrosine kinases, would inhibit the growth of cutaneous squamous cell carcinom...

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Veröffentlicht in:Clinical cancer research 2005-03, Vol.11 (5), p.1963-1973
Hauptverfasser: Park, Young Wook, Younes, Maher N, Jasser, Samar A, Yigitbasi, Orhan G, Zhou, Ge, Bucana, Corazon D, Bekele, Benjamin N, Myers, Jeffrey N
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Sprache:eng
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Zusammenfassung:Purpose: We investigated whether concomitant blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways by AEE788, a dual inhibitor of EGFR and VEGFR tyrosine kinases, would inhibit the growth of cutaneous squamous cell carcinoma (SCC) cells and human cutaneous cancer xenografts in nude mice. Experimental Design: We examined the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in cutaneous SCC cells expressing EGFR and VEGFR-2 and cutaneous SCC cell growth and apoptosis. We assessed the in vivo antitumor effects of AEE788 in a xenograft model in nude mice. AEE788 (50 mg/kg) was given orally thrice weekly to mice that had been s.c. injected with Colo16 tumor cells. Mechanisms of in vivo AEE788 activity were determined by immunohistochemical analysis. Results: Treatment of cutaneous SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. In mice treated with AEE788, tumor growth was inhibited by 54% at 21 days after the start of treatment compared with control mice ( P < 0.01). Immunohistochemical analysis revealed that AEE788 inhibited phosphorylation of EGFR and VEGFR and induced apoptosis of tumor cells and tumor-associated endothelial cells. Conclusions: In addition to inhibiting cutaneous cancer cell growth by blocking EGFR and VEGFR signaling pathways in vitro , AEE788 inhibited in vivo tumor growth by inducing tumor and endothelial cell apoptosis.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-04-1665