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• W2055209074 abstract "The epidermal growth factor receptor (EGFR) is overexpressed in many tumours and is a target for cancer therapy. Cetuximab is a monoclonal antibody targeting EGFR. It is used for the treatment of metastatic colorectal cancer (mCRC) as monotherapy and in combination with oxaliplatin or irinotecan-based chemotherapy. Several clinical studies have shown no benefit when cetuximab is combined with oxaliplatin as opposed to the positive effects observed with irinotecan. The aim of this study is to investigate these interactions in cellular models of colon cancer. The antitumour effects of cetuximab in vitro in combination with oxaliplatin or irinotecan were determined in the SW 48 colon cancer cell line and the isogenic KRAS mutant G12A cell line. Combination indices (CI) describing the interaction of a fixed concentration of cetuximab and a range of concentrations of oxaliplatin or irinotecan were determined. Combination of cetuximab (100μg/ml) with oxaliplatin (1μM) indicated antagonism in both cell lines tested (CI=4.7 in the KRAS wild type cell line and CI=19.9 in the KRAS G12A cell line). In contrast, the combination of cetuximab (100μg/ml) with irinotecan (0.1μM) showed synergistic effects (CI=0.28 in the KRAS wild type cell line and CI=0.14 in the KRAS G12A cell line). Preclinical studies have suggested that the cytotoxic efficacy of oxaliplatin may depend partially on the production of Reactive Oxygen Species (ROS). The combination of cetuximab with oxaliplatin resulted in a reduction of ROS levels by 30% ± 2.9 in the KRAS WT and by 40% ± 10 in the KRAS G12A cell line compared to those produced by oxaliplatin alone. Additionally, levels of oxaliplatin-induced apoptosis measured by caspase 3/7 cleavage, were reduced by 70% ± 5.4 in the KRAS WT and by 50% ± 2.7 in the KRAS G12A cell line with the antioxidant N-acetyl-cysteine (NAC), suggesting that oxaliplatin induces apoptosis through the production of ROS. To elucidate the mechanism of the modulation of ROS by cetuximab and oxaliplatin, RT-PCR arrays analyzing 84 genes involved in oxidative stress response were performed following cetuximab, oxaliplatin and their combination treatment. Experiments to determine the contribution of these genes to the antagonism between oxaliplatin and cetuximab are under investigation. Our results show that alteration of ROS levels by cetuximab affects efficacy of oxaliplatin and suggests a key role for ROS in the observed antagonism between the two drugs. Citation Format: Valeria Santoro, John A. Hartley, Daniel Hochhauser. Interaction between cetuximab and chemotherapy in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2013-5468" @default.
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• W2055209074 date "2013-04-15" @default.
• W2055209074 modified "2023-09-25" @default.
• W2055209074 title "Abstract 5468: Interaction between cetuximab and chemotherapy in colon cancer." @default.
• W2055209074 doi "https://doi.org/10.1158/1538-7445.am2013-5468" @default.
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