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Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models


Oehler-Jänne, Christoph; Jochum, Wolfram; Riesterer, Oliver; Broggini-Tenzer, Angela; Caravatti, Giorgio; Vuong, Van; Pruschy, Martin (2007). Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models. Molecular Cancer Therapeutics, 6(9):2496-2504.

Abstract

Concomitant inhibition of ErbB1/2- and VEGF receptor-signaling synergizes when used in combination with DNA-damaging agents. Here, we investigated for the first time the combined treatment modality of the novel dual specific receptor tyrosine kinase inhibitor AEE788 with ionizing radiation and analyzed treatment-induced end points in situ as indicators for a potential sensitizing mechanism. Furthermore, we assessed tumor hypoxia in response to different antiangiogenic and antiproliferative treatment modalities. The combined treatment effect was investigated in a spontaneously growing mammary carcinoma model and against Her-2/neu-overexpressing mammary carcinoma allografts. In tumor allografts derived from murine mammary carcinoma cells of mouse mammary tumor virus/c-neu transgenic mice, a minimal treatment regimen with AEE788 and fractionated irradiation resulted in an at least additive tumor response. Treatment response in the corresponding spontaneous tumor model strongly exceeded the response induced in the isogenic allografts. Treatment-induced changes of tumor proliferation, apoptosis, and microvessel density were similar in the two tumor models. Treatment with AEE788 alone or in combination with IR strongly improved tumor oxygenation in both tumor models as determined by the detection of endogenous and exogenous markers of tumor hypoxia. Specific inhibition of the VEGF-receptor tyrosine kinase versus Erb1/2-receptor tyrosine kinase indicated that it is the antiproliferative and not the antiangiogenic potency of AEE788 that mediates the hypoxia-reducing effect of this dual kinase-specific inhibitor. Overall, we show that concomitant inhibition of ErbB- and VEGF-receptor signaling by AEE788, in combination with ionizing radiation, is a promising treatment approach, especially in hypoxic, oncogenic ErbB-driven tumors.

Abstract

Concomitant inhibition of ErbB1/2- and VEGF receptor-signaling synergizes when used in combination with DNA-damaging agents. Here, we investigated for the first time the combined treatment modality of the novel dual specific receptor tyrosine kinase inhibitor AEE788 with ionizing radiation and analyzed treatment-induced end points in situ as indicators for a potential sensitizing mechanism. Furthermore, we assessed tumor hypoxia in response to different antiangiogenic and antiproliferative treatment modalities. The combined treatment effect was investigated in a spontaneously growing mammary carcinoma model and against Her-2/neu-overexpressing mammary carcinoma allografts. In tumor allografts derived from murine mammary carcinoma cells of mouse mammary tumor virus/c-neu transgenic mice, a minimal treatment regimen with AEE788 and fractionated irradiation resulted in an at least additive tumor response. Treatment response in the corresponding spontaneous tumor model strongly exceeded the response induced in the isogenic allografts. Treatment-induced changes of tumor proliferation, apoptosis, and microvessel density were similar in the two tumor models. Treatment with AEE788 alone or in combination with IR strongly improved tumor oxygenation in both tumor models as determined by the detection of endogenous and exogenous markers of tumor hypoxia. Specific inhibition of the VEGF-receptor tyrosine kinase versus Erb1/2-receptor tyrosine kinase indicated that it is the antiproliferative and not the antiangiogenic potency of AEE788 that mediates the hypoxia-reducing effect of this dual kinase-specific inhibitor. Overall, we show that concomitant inhibition of ErbB- and VEGF-receptor signaling by AEE788, in combination with ionizing radiation, is a promising treatment approach, especially in hypoxic, oncogenic ErbB-driven tumors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2007
Deposited On:24 Jul 2015 10:49
Last Modified:05 Apr 2016 19:19
Publisher:American Association for Cancer Research
ISSN:1535-7163
Publisher DOI:https://doi.org/10.1158/1535-7163.MCT-07-0253
PubMed ID:17876047

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