Unusually marked hypoxic sensitization to indoloquinone E09 and mitomycin C in a human colon-tumour cell line that lacks DT-diaphorase activity
✍ Scribed by Jane A. Plumb; Paul Workman
- Book ID
- 102864452
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- French
- Weight
- 685 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone E 0 9 to a DNA-damaging alkylating species. The aim of this study was to determine to what extent DT-diaphorase may be involved in the metabolic activation of E09 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; H l 2 9 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOl gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of qtotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but H R 9 is more sensitive than BE to mitomycin C and E09. Sensitivity to SR 4233 is increased by about 100-fold for both cell lines in hypoxic conditions. DT-diaphorase-deficient BE cells show markedly increased sensitivity to mitomycin C and particularly E 0 9 in hypoxic conditions, whereas DTdiaphorase-rich H R 9 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol.
These results suggest that DT-diaphorase can reduce E09 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activii predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DTdiaphorase activity, E 0 9 and mitomycin C are reduced in hypoxic conditions, presumably by one-electron-reducing enzymes, to a similar or greater extent than is achieved with DT-diaphorase.