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Cancer Lett. 2012 Jul 1;320(1):56-64. doi: 10.1016/j.canlet.2012.01.025. Epub 2012 Jan 20.

Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment.

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  • 1Department of Gastroenterology, Charit√© Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.

Abstract

The role of mismatch repair (MMR) in the response of colon carcinoma cells to 5-fluorouracil (5FU) is not well understood. In most of the in vitro studies only short-term response was investigated. We focussed here on the influence of MMR status on the mechanism of the short- and long-term response to clinically relevant 5FU concentrations by using isogenic or semiisogenic cell line pairs expressing/nonexpressing the hMLH1 protein, an important component of the MMR system. We show that the lower survival of MMR-proficient than of MMR-deficient cells in the clonogenic survival assay is due to a more frequent early cell arrest and to subsequent senescence. By contrast, the long-term cell growth after treatment, which is also affected by long-term arrest and senescence, is independent from the MMR status. The overall effect on the long-term cell growth is a cumulative result of cell proliferation rate-dependent growth inhibition, apoptosis and necrotic cell death. The main long-term cytotoxic effect of 5FU is the inhibition of growth while apoptosis and the necrotic cell death are minor contributions.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

PMID:
22266192
[PubMed - indexed for MEDLINE]
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