title: Cytotoxicity and mutagenicity of frameshift-inducing agent ICR191 in mismatch repair-deficient colon cancer cells.
abstract: BACKGROUND
  Deficiency of DNA mismatch repair is a common feature of cancers exhibiting instability of microsatellite DNA sequences. Cancers with microsatellite instability are recognizable by their high rate of spontaneous frameshift mutations within microsatellite sequences, their resistance to killing by cytotoxic agents, and their localization to specific tissues, e.g., the proximal colon and stomach. We hypothesized that the mismatch repair deficiency of these cancers would make them vulnerable to environmental or chemical frameshift-inducing agents. This study was undertaken to test whether exogenous frameshift-inducing agents selectively induce mutations in mismatch repair-deficient cells of mutagen-exposed tissues like the colon and whether cytotoxic doses of these agents would preferentially kill those cells.
  
  
  METHODS
  Cytotoxicity of the acridine mutagen 6-chloro-9-[3-(2-chloroethylamino)propylamino]-2-methoxy-acridine (ICR191), a DNA frameshift inducer, was determined in the mismatch repair-deficient human colon carcinoma cell line HCT116 versus the repair-reconstituted derivative HCT116+C3. Vulnerability to the mutagenic effects of ICR191 was determined by transfection of HCT116 or HCT116+C3 cells with a frameshift reporter vector, followed by treatment of the cells with ICR191. Alternatively, the reporter vector was reacted ex vivo with ICR191, and the derivatized vector was then transfected into HCT116 or HCT116+C3 cells.
  
  
  RESULTS
  ICR191 proved to be fivefold to 10-fold more potent in inducing mutations in mismatch repair-deficient HCT116 cells than in mismatch repair-proficient HCT116+C3 cells. Moreover, at cytotoxic doses of ICR191, repair-deficient HCT116 cells proved to be fivefold more vulnerable to killing than did HCT116+C3 cells.
  
  
  CONCLUSIONS
  Frameshift-inducing mutagens can selectively induce mutations in mismatch repair-deficient cells versus mismatch repair-proficient cells. Environmental exposures may, therefore, favor development of cancers with microsatellite instability in tissues like the gut. Frameshift-inducing agents can, however, also preferentially kill mismatch repair-deficient cancer cells and, thus, may be promising as model therapeutic compounds.
authors.affiliation: Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, OH, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Chen
authors.forename: J R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: M R
authors.initials: MR
authors.lastname: Aminoshariae
authors.forename: A H
authors.initials: AH
authors.lastname: Ma
authors.forename: N
authors.initials: N
authors.lastname: Veloso
authors.forename: S D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: W D
authors.initials: WD
authors.lastname: Sedwick
authors.forename: M L
authors.initials: ML
authors.lastname: Veigl
mesh_terms: D000585:Aminacrine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D020137:Base Pair Mismatch / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D016368:Frameshift Mutation / Q000187:drug effects*; D006801:Humans; D018895:Microsatellite Repeats / Q000187:drug effects; D009153:Mutagens / Q000009:adverse effects* / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009153:Mutagens; D009588:Nitrogen Mustard Compounds; D000585:Aminacrine; C004294:acridine half-mustard