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| UNUSUALLY MARKED HYPOXIC SENSITIZATION TO INDOLOQUINONE EO9 AND MITOMYCIN-C IN A HUMAN COLON-TUMOR CELL-LINE THAT LACKS DT-DIAPHORASE ACTIVITY |
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| Author(s): PLUMB JA, WORKMAN P |
| Source: INTERNATIONAL JOURNAL OF CANCER Volume: 56 Issue: 1 Pages: 134-139 Published: JAN 2 1994 |
| Times Cited: 65 References: 37 |
| Abstract: Studies with purified DT-diaphorase have shown that the enzyme is capable of catalyzing a two-electron reduction of the novel indoloquinone EO9 to a DNA-damaging alkylating species. The aim of this study war to determine to what extent DT-diaphorase may be involved in the metabolic activation of EO9 and mitomycin C in both aerobic and hypoxic conditions. Two human colon-carcinoma cell lines were used; HT29 has high levels of DT-diaphorase whilst BE lacks this activity because of a point mutation in the NQOI gene. In aerobic conditions the 2 cell lines show similar sensitivities to a number of cytotoxic drugs including cisplatin, doxorubicin and etoposide. They are equally sensitive to the benzotriazine di-N-oxide SR 4233 but HT29 is more sensitive than BE to mitomycin C and EO9. 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 EO9 in hypoxic conditions, whereas DT-diaphorase-rich HT29 cells show little hypoxic sensitization to these agents unless exposed in the presence of dicoumarol. These results suggest that DT-diaphorase can reduce EO9 and mitomycin C to potent cytotoxic species in aerobic conditions, and this activity predominates over the one-electron-reducing enzymes even in hypoxic conditions. In the absence of DT-diaphorase activity, EO9 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. (C) 1994 Wiley-Liss, Inc. |
| Document Type: Proceedings Paper |
| Language: English |
| Reprint Address: PLUMB, JA (reprint author), UNIV GLASGOW, CRC, DEPT MED ONCOL, BEATSON LABS, GARSCUBE ESTATE, GLASGOW G61 1BD, SCOTLAND |
| Publisher: WILEY-LISS, DIV JOHN WILEY & SONS INC 605 THIRD AVE, NEW YORK, NY 10158-0012 |
| Subject Category: Oncology |
| IDS Number: MP711 |
| ISSN: 0020-7136 |
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