Cytotoxicity and mutagenicity of frameshift-inducing agent ICR191 in mismatch repair-deficient colon cancer cells

Background: Deficiency of DNA mismatch repair is a common feature of cancer s exhibiting instability of microsatellite DNA sequences. Cancers with micr osatellite instability are recognizable by their high rate of spontaneous f rameshift mutations within microsatellite sequences, their resistance to ki lling 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 whet her exogenons frameshift-inducing agents selectively induce mutations in mi smatch repair-deficient cells of mutagen-exposed tissues like the colon and whether cytotoxic doses of these agents would preferentially kill those ce lls. Methods: Cytotoxicity of the acridine mutagen 6-chloro-9-[3-(2-chloroe thylamino)propylamino]-2-methoxy-acridine (ICR191), a DNA frameshift induce r, was determined in the mismatch repair-deficient human colon carcinoma ce ll line HCT116 versus the repair-reconstituted derivative HCT116+C3. Vulner ability to the mutagenic effects of ICR191 was determined by transfection o f 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 transfecte d into HCT116 or HCT116+C3 cells, Results: ICR191 proved to be fivefold to 10-fold more potent in inducing mutations in mismatch repair-deficient HCT1 16 cells than in mismatch repair-proficient HCT116+C3 cells. Moreover, at c ytotoxic doses of ICR191, repair-deficient HCT116 cells proved to be fivefo ld more vulnerable to killing than did HCT116+C3 cells. Conclusions: Frames hift-inducing mutagens can selectively induce mutations in mismatch repair- deficient cells versus mismatch repair-proficient cells. Environmental expo sures may, therefore, favor development of cancers with microsatellite inst ability In tissues like the gut. Frameshift-inducing agents can, however, a lso preferentially kill mismatch repair-deficient cancer cells and, thus, m ay be promising as model therapeutic compounds.