Induction of DT-diaphorase by 1,2-dithiole-3-thiones and the enhancement of antitumour activity of bioreductive agents

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Doherty, Geoffrey P.
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DT-diaphorase is a two-electron reducing enzyme that is an important activator of bioreductive antitumour agents, such as mitomycin C and EO9. DT-diaphorase is highly inducible by a wide variety of compounds, including 1,2-dithiole-3-thiones (D3T's), and these compounds could be used to enhance the antitumour activity of bioreductive agents. We investigated the ability of D3T to increase the level of DT-diaphorase activity in human tumour cells lines and normal human cells. D3T significantly increased DT-diaphorase activity in 11 of 18 human tumour cell lines representing 6 tissue types. There were no obvious relationships between the tumour type, or the basal level of DT-diaphorase activity in the cells, and the ability of D3T to increase the enzyme activity. Tumour cells of all tissue types were induced except head and neck tumour cells and hepatoma cells. DT-diaphorase was induced by D3T in normal human bone marrow, kidney, and lung cells, but the increases were small in the marrow and kidney cells. We examined the ability of 13 D3T analogs to induce DT-diaphorase activity in 8 human tumour cell lines from 5 different tissues. The parent D3T appeared to be the best overall inducer of DT-diaphorase in the cell lines studied, but induction of enzyme activity varied markedly with the D3T structure. D3T increased tumour cell kill by EO9 in HL-60 human leukemia cells and this was inhibited by an inhibitor of DT-diaphorase, dicoumarol. In contrast, D3T had no effect on EO9 cell kill in normal human kidney cells, the site of dose-limiting toxicity for EO9 therapy. (Abstract shortened by UMI.)