INDUCTION OF DT-DIAPHORASE BY 1,2-DITHIOLE-3-THIONES IN HUMAN TUMOR AND NORMAL-CELLS AND EFFECT ON ANTITUMOR-ACTIVITY OF BIOREDUCTIVE AGENTS

DT-diaphorase is a two-electron-reducing enzyme that is an important a ctivator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and EO9, and is inducible by many compounds, including 1,2-dithiole-3 -thiones (D3Ts). We showed previously that D3T selectively increased D T-diaphorase activity in mouse lymphoma cells compared with normal mou se marrow cells, and also increased MMC or EO9 cytotoxic activity in t he lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activi ty in 28 of 38 human tumour cell lines representing ten tissue types w ith no obvious relationships between the tumour type, or the base leve l of DT-diaphorase activity, and the ability of D3T to increase the en zyme activity. Induction of DT-diaphorase activity in human tumour cel l lines by 12 D3T analogues varied markedly with the D3T structure. D3 T also increased DT-diaphorase activity in normal human bone marrow an d kidney cells but the increases were small in these cells. In additio n, D3T increased the level of enzyme activity in normal human lung cel ls. Pretreatment of human tumour cells with D3T analogues significantl y increased the cytotoxic activity of MMC or EO9 in these cells, and t he level of enhancement of anti-tumour activity paralleled the level o f DT-diaphorase induction. In contrast, D3T did not effect the toxicit y of EO9 in normal kidney cells. These results demonstrate that D3T an alogues can increase DT-diaphorase activity in a wide variety of human tumour cells and that this effect can enhance the anti-tumour activit y of the bioreductive agents MMC and EO9.