Induction of DT-diaphorase by 1,2-dithiole-3-thione and increase of antitumour activity of bioreductive agents.

Abstract

Bioreductive antitumour agents are an important new class of anticancer drugs that require activation by reduction. The two-electron reducing enzyme, DT-diaphorase, has been shown to be an important activating enzyme for the bioreductive agents, mitomycin C (MMC) and EO9. Incubation of L5178Y murine lymphoma cells in vitro with 1,2-dithiole-3-thione (D3T) increased the level of DT-diaphorase activity in these cells 22-fold. In contrast, D3T had no effect on the DT-diaphorase level in normal mouse bone marrow cells. Combination therapy with D3T and MMC or EO9, produced a 2- or 7-fold enhancement, respectively, of the cytotoxic 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-diaphorase inhibitor, dicoumarol, inhibited the effect of D3T on the antitumour activity of the bioreductive agents, supporting the proposal that the enhanced anticancer activity was due to the elevated enzyme level. These findings suggest that D3T, or other inducers of DT-diaphorase, could be used to enhance the antitumour efficacy of bioreductive antitumour agents.