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  • Title: The importance of DT-diaphorase in mitomycin C resistance in human colon cancer cell lines.
    Author: Lambert PA, Kang Y, Greaves B, Perry RR.
    Journal: J Surg Res; 1998 Dec; 80(2):177-81. PubMed ID: 9878310.
    Abstract:
    BACKGROUND: Prior studies have suggested the multifactorial nature of mitomycin C (MMC) resistance. However, the relative importance of the different resistance mechanisms is unknown. MATERIALS AND METHODS: A panel of colon cancer cell lines with levels of MMC resistance from 2- to 15-fold compared to the parent line HT-29 was produced by repeated MMC exposure. Cell survival was measured using clonogenic assay. Glutathione and related enzymes and DT-diaphorase were measured using biochemical assays. P-glycoprotein expression was measured using flow cytometry. Topoisomerase II activity was measured using the pBR322 DNA relaxation assay. RESULTS: Multiple drug resistance mechanisms were altered in the resistant cell lines (glutathione reductase, glutathione peroxidase, topoisomerase II). However, the level of DT-diaphorase correlated best with the degree of MMC resistance. The importance of DT-diaphorase was confirmed by using BMY 25282, an MMC analogue which is less dependent on DT-diaphorase for activation. Resistance in the HT-29R54 cell line was 15-fold with MMC compared to 5-fold with BMY 25282. P-glycoprotein-mediated resistance does not appear important in this model. CONCLUSIONS: Although MMC resistance appears to be multifactorial, the results of this study strongly suggest that DT-diaphorase is the major contributor to MMC resistance under aerobic conditions. Strategies to enhance drug activation may therefore be useful for reversing MMC resistance.
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