alexa Cetuximab inhibits thymidylate synthase in colorectal cells expressing epidermal growth factor receptor.


Journal of Gastrointestinal & Digestive System

Author(s): Skvortsov S, Sarg B, Lindner H, Lukas P, Hilbe W,

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Abstract The monoclonal antibody cetuximab directed against the epidermal growth factor receptor (EGFR) is an attractive agent for targeted therapy in advanced colorectal cancer (CRC), especially when combined with 5-fluorouracil (5-FU)-based chemotherapy. However, the mechanisms of cetuximab activity as chemosensitizer remain poorly understood. Using proteome-fluorescence-based technology, we found that cetuximab is able to suppress the expression of thymidylate synthase (TS), which is involved in the mechanism of 5-FU action. Caco-2, HRT-18, HT-29, WiDr and SW-480 CRC cells were found to express EGFR. SW-620 was used as EGFR-negative cell line. Only in EGFR-expressing cells cetuximab is able to inhibit TS expression. Combined treatment with cetuximab and 5-FU revealed a synergistic anti-tumor response that is closely correlated with functional activity of EGFR/mitogen-activated protein kinase (MAPK) pathway. Moreover, no correlation was seen between constitutive TS protein expression, level of cetuximab-induced TS down-regulation and response either to 5-FU alone or in combination with cetuximab. We demonstrated that only EGFR expression with high functional activity of EGFR/MAPK pathway is important for the synergistic effects between cetuximab and 5-FU in the investigated cell lines. Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This article was published in Proteomics Clin Appl and referenced in Journal of Gastrointestinal & Digestive System

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