INDUCTION OF DT-DIAPHORASE BY 1,2-DITHIOLE-3-THIONE AND INCREASE OF ANTITUMOR-ACTIVITY OF BIOREDUCTIVE AGENTS

Bioreductive antitumour agents are an important new class of anticance r drugs that require activation by reduction. The two-electron reducin g enzyme, DT-diaphorase, has been shown to be an important activating enzyme for the bioreductive agents, mitomycin C (MMC) and EO9. Incubat ion of L5178Y murine lymphoma cells in vitro with 1,2-dithiole-3-thion e (D3T) increased the level of DT-diaphorase activity in these cells 2 2-fold. In contrast, D3T had no effect on the DT-diaphorase level in n ormal mouse bone marrow cells. Combination therapy with D3T and MMC or EO9, produced a 2- or 7-fold enhancement, respectively, of the cytoto xic activity of these antitumour agents in L5178Y cells. By comparison , D3T did not enhance the activity of MMC in marrow cells and produced only a small increase in EO9 cytotoxicity in these cells. The DT-diap horase inhibitor, dicoumarol, inhibited the effect of D3T on the antit umour activity of the bioreductive agents, supporting the proposal tha t the enhanced anticancer activity was due to the elevated enzyme leve l. These findings suggest that D3T, or other inducers of DT-diaphorase , could be used to enhance the antitumour efficacy of bioreductive ant itumour agents.