Effect of DT-diaphorase induction on the anti-tumor activity of RH1 and mitomycin C

DT-diaphorase is a reductive enzyme that is important for the activation of many bioreductive agents and is a target for an enzyme directed approach to cancer therapy. It can be selectively induced in many tumor types by a number of compounds including dimethyl fumarate (DMF) and sulforaphane. Mitomycin C (MMC) is a bioreductive agent that is used clinically for treatment of solid tumors. RH1 (2,5-diaziridinyl-3-3[hydroxymethyl]-6-methyl-1,4-benzoquinone) is a new bioreductive agent currently in clinical trials. We have shown previously that inducers of DT-diaphorase can enhance the antitumor activity of MMC in tumor cells in vitro and in vivo. As RH1 is activated selectively by DT-diaphorase while MMC is activated by many reductive enzymes, we investigated whether induction of DT-diaphorase would produce a greater enhancement of the antitumor activity of RH1 compared with MMC.; The ability of RH1 to cross-link DNA in the presence and absence of DT-diaphorase was examined. Double stranded DNA was incubated with RH1 with, and without, DT-diaphorase and cross-linking was assessed by a gel assay. RH1 produced DNA cross-links only in the presence of DT-diaphorase. These results indicate that RH1 must be reduced to form cross-links and that DT-diaphorase is capable of carrying out this reduction. (Abstract shortened by UMI.)...