© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 6, 480-485,
March 15, 2000
© 2000 Oxford University Press
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Cytotoxicity and Mutagenicity of Frameshift-Inducing Agent ICR191 in Mismatch Repair-Deficient Colon Cancer Cells
Affiliations of authors: W.-D. Chen, M. R. Aminoshariae, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, OH; J. R. Eshleman, Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD; A.-H. Ma, N. Veloso, Environmental Health Sciences Department, Case Western Reserve University; S. D. Markowitz, Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland; W. D. Sedwick, Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland; M. L. Veigl, Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland.
Correspondence to: Sanford D. Markowitz, M.D., Ph.D., Howard Hughes Medical Institute, U.C.R.C. #2, Suite 200, 11001 Cedar Rd., Cleveland, OH 44106 (e-mail: sxm10{at}po.cwru.edu).
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.
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