Enhancement of antitumour activity and structure-activity study of bioreductive agents

Abstract

DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive antitumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. This study demonstrates that induction of DT-diaphorase can increase the cytotoxic activity of MMC in human tumour cell lines and suggests that it may be possible to use non-toxic inducers of DT-diaphorase to enhance the efficacy of bioreductive antitumour agents. Bioreductive antitumour agents are uniquely suited to the improvement of tumour selectivity by an "enzyme-directed" approach to tumour targeting. However, none of the bioreductive agents developed to date have been specific for activation by a single reductive enzyme, in part, due to a lack of knowledge of structural factors that produce selectivity for activation by reductive enzymes. We used a series of model benzoquinone mustard bioreductive agents to investigate the role of functional groups in modifying the specificity for drug activation byDT-diaphorase. We compared the parent agent, benzoquinone mustard (BM), with a series of analogues having different functional groups in their structures to identify structure-activity relationships. We found that methoxy, phenyl and chloro functional groups decreased the rate of reduction of the quinone group by DT-diaphorase. The methoxy group resulted in DT-diaphorase becoming an activating enzyme for 5-methoxy-BM (MBM) compared to an inactivation enzyme for BM. The functional groups also affected the ability of the reduced product to undergo redox cycling. (Abstract shortened by UMI.)