[DT-diaphorase].
Anti-tumor quinone, including mitomycin C (MMC), needs to be activated by bioreduction to exert its cytotoxic activities. The enzymes underlying this bioreductive activation have been the subject of extensive research on Mitomycin C. Cytochrome P450 reductase, cytochrome b5 reductase, xanthine oxidase, xanthine dehydrogenase and DT-diaphorase (DTD) have been shown to be involved in the reduction of MMC. The relationship between bioreductive enzymes and the cytotoxicity of quinone, however, has not been analyzed yet. In this study, we investigated the relationship between the bioreductive enzymes and the cytotoxicity of MMC. We carried out the following experiments and the following results were obtained. I) We isolated an MMC-resistant variant. This cell showed five-fold resistance to MMC as compared with the parental cell line. DTD was deficient in this resistant cell. II) We have examined the bioreductive enzyme activities of DTD and cytochrome P450 reductase and IC50's of MMC in 13 colon and gastric carcinoma cell lines. A positive correlation was not found between the enzyme activities and MMC sensitivities, but the cells with little or no DTD activity showed higher IC50 values compared to the other cell lines. III) To elucidate directly the role of DTD in MMC sensitivity, we introduced NQO1 gene into St-4 cells. NQO1 gene encodes DTD and St-4 cells have no DTD activity. All of the transfectants showed five- to ten-fold higher sensitivity to MMC as compared to the parental St-4 cells. The above data indicate that DTD is a critical determinant of sensitivity to MMC in aerobic conditions.
Mikami
K
K
Institute of Molecular and Cellular Biosciences, University of Tokyo.
Shirakusa
T
T
Tsuruo
T
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D003579:Cytochrome Reductases / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology*; D008937:Mitomycins; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D013274:Stomach Neoplasms / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D009247:NADH, NADPH Oxidoreductases; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); C060817:apaziquone