Journal Article

Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells

Warren E. Glaab, Rosina B. Hill and Thomas R. Skopek

in Carcinogenesis

Volume 22, issue 10, pages 1709-1713
Published in print October 2001 | ISSN: 0143-3334
Published online October 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.10.1709
Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells

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Genomic instability associated with deficiencies in mismatch repair (MMR) plays a critical role in tumorigenesis. Here we have investigated the contribution of oxidative damage to this instability in MMR-defective cells. Treatment with H2O2 produced less cytotoxicity in MMR-deficient cells than in those proficient in MMR, supporting a role for MMR in the recognition and/or processing of oxidative damage. Additionally, growth of MMR-defective cells in the presence of the antioxidant ascorbate (500 μM) reduced the spontaneous mutation rate at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus by up to 50% and reduced microsatellite instability by 30%. Induction of HPRT mutants by exogenously added H2O2 was also significantly suppressed by ascorbate. Collectively, these results suggest that (i) oxidative damage contributes significantly to the spontaneous mutator phenotype in MMR-defective cells, (ii) this damage may select for MMR-deficient cells due to their increased resistance to cell killing and (iii) dietary antioxidants may help to suppress the mutator phenotype and resulting carcinogenesis in individuals with compromised MMR.

Keywords: DMSO, dimethyl sulfoxide; HBSS, Hanks' balanced salt solution; HPRT, hypoxanthine-guanine phosphoribosyl transferase locus; MMR, mismatch repair; 8-oxo-G, 8-oxoguanine; 6-TG, 6-thioguanine.

Journal Article.  4193 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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