Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

Br J Cancer. 2008 Nov 18;99(10):1607-12. doi: 10.1038/sj.bjc.6604691. Epub 2008 Oct 21.

Abstract

Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC(50) and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted.

Publication types

  • Comparative Study

MeSH terms

  • Acid Anhydride Hydrolases
  • Adaptor Proteins, Signal Transducing / genetics*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Cell Line, Tumor / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Cytotoxins / pharmacology
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics
  • Humans
  • Irinotecan
  • MRE11 Homologue Protein
  • Microsatellite Instability*
  • MutL Protein Homolog 1
  • Nuclear Proteins / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Phytogenic
  • Cytotoxins
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • MRE11 protein, human
  • Nuclear Proteins
  • Irinotecan
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • MutL Protein Homolog 1
  • DNA Repair Enzymes
  • Camptothecin