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Mismatch repair proficiency and in vitro response to 5-fluorouracil

J M Carethers1, D P Chauhan, D Fink

  • 1Department of Medicine, University of California, USA. jcarethers@ucsd.edu

Gastroenterology
|June 26, 1999
PubMed
Abstract

Insights

DNA mismatch repair (MMR) deficiency confers colon cancer cell tolerance to 5-fluorouracil (5-FU). MMR-deficient cells showed enhanced survival, suggesting defective MMR as a resistance mechanism to 5-FU chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The DNA mismatch repair (MMR) system corrects DNA errors, including those from alkylation damage and microsatellite instability.
  • Defects in MMR can lead to tolerance of DNA damage and chemotherapy agents.
  • The role of MMR in response to 5-fluorouracil (5-FU) in colon cancer was investigated.

Purpose of the Study:

  • To investigate the effect of 5-fluorouracil (5-FU) on colon cancer cell lines with varying DNA mismatch repair (MMR) proficiency.
  • To determine if MMR status influences cellular response and tolerance to 5-FU treatment.

Main Methods:

  • Colon cancer cell lines were treated with 5 micromol/L 5-FU.
  • Growth selection was assessed using cell enrichment assays and cloning efficiency.
  • Nucleic 5-FU incorporation and cell cycle progression were analyzed via radiolabeling and flow cytometry.

Main Results:

  • MMR-deficient colon cancer cell lines exhibited a significant growth advantage and enhanced survival when treated with 5-FU.
  • MMR-proficient cells showed a substantial reduction in survival after 10 days of 5-FU exposure.
  • Observed growth differences were not attributable to variations in 5-FU nucleotide uptake or cell cycle arrest.

Conclusions:

  • Intact DNA MMR appears to recognize 5-FU incorporated into DNA, potentially via a distinct mechanism compared to other alkylation damage.
  • Defective DNA MMR may represent a key mechanism contributing to tumor resistance against 5-FU chemotherapy.

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