[Mitomycin C and its bioreduction: relevance of NAD(P)H: quinone oxidoreductase activity to mitomycin C-induced DNA damage and cytotoxicity].
Using 4 human cancer cell lines, the relevance of NAD(P)H: quinone oxidoreductase (DT-diaphorase) activity to mitomycin C (MMC)-induced cytotoxicity was investigated. KB cells (oral epidermoid carcinoma) had more than 4 times higher DT-diaphorase activity than PH101 (pancreatic cancer), SH 101 (gastric cancer), or K562 (myelogenous leukemia) cells. The sensitivity to MMC was greatest in KB cells. Concentrations causing 50% inhibition of cell growth (IC50 value: microgram/ml) by 30 min treatment with MMC were 0.4 in KB, 1.1 in PH101, 1.6 in SH 101, and 1.9 in K 562. Treatment with 1.5 micrograms/ml of MMC induced DNA total cross links, and the indices were 0.18 in KB, 0.10 in SH101, 0.09 in SH101, and 0.06 in K 562. When DT-diaphorase activity was inhibited by non-toxic dicoumarol (50 microM), DNA damage and cytotoxic activity induced by MMC were decreased in all cells examined. Especially in KB cells, it was remarkable. Since it was shown that the level of cellular DT-diaphorase activities were correlated with the responses to MMC, we suggest that bioreduction by DT-diaphorase may activate MMC.
Nishiyama
M
M
Dept. of Surgery, Hiroshima University.
Saeki
S
S
Aogi
K
K
Hirabayashi
N
N
Toge
T
T
D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000473:pathology; D016685:Mitomycin / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000201:enzymology / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D016685:Mitomycin; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone)