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The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.

Sini, Patrizia and Wyder, Lorenza and Schnell, Christian and O'Reilly, Terence and Littlewood-Evans, Amanda Jane and Brandt, Ralph and Hynes, Nancy E. and Wood, Jeanette (2005) The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clinical cancer research : an official journal of the American Association for Cancer Research, 11 (12). pp. 4521-4532. ISSN 1078-0432

Abstract

PURPOSE: Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment. EXPERIMENTAL DESIGN: The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells. RESULTS: Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ZK222584. In vitro, ErbB1 inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release of VEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting. CONCLUSION: We have shown that activation of ErbB1 triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1 and VEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy.

Item Type: Article
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Additional Information: free final full text version available at publisher's official URL; authors final version may be deposited on institutional website/ repository if required by institution
Keywords: Epidermal growth factor receptor; endothelial cells; smooth muscle cells; receptor tyrosine kinase; angiogenesis
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Date Deposited: 14 Dec 2009 14:07
Last Modified: 31 Jan 2013 01:32
URI: https://oak.novartis.com/id/eprint/32

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