title: Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment.
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.
authors.affiliation: Department of Gastroenterology, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Choudhary
authors.forename: M L
authors.initials: ML
authors.lastname: Hanski
authors.forename: M
authors.initials: M
authors.lastname: Zeitz
authors.forename: C
authors.initials: C
authors.lastname: Hanski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000502:physiology*; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D007770:L-Lactate Dehydrogenase; D000070957:MutL Protein Homolog 1; D005472:Fluorouracil