Enzyme-directed bioreductive drug development revisited: a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolizing enzymes, particularly DT-diaphorase.

The enzyme-directed approach to bioreductive drug development is designed to take advantage of the fact that the selectivity of bioreductive anticancer agents can be governed not only by the well-established difference in oxygen content of tumour vs. normal tissues, but also by the level of expression of enzymes catalyzing the reductive activation process. This can add value to bioreductive drug development in two ways. First, by using enzyme profiling to help guide the selection of patients most likely to respond to a particular bioreductive agent. And second, to aid the discovery of new and improved bioreductive drugs by optimising structure to suit the catalytic preferences of a given reductase enzyme. In this commentary, recent progress in the area of enzyme-directed bioreductive drug development is reviewed with emphasis on quinone anticancer agents and quinone reducing enzymes, particularly DT-diaphorase, which is often hyperexpressed in cancer tissue. The enzyme-directed approach has led to the development of the indoloquinone EO9, which is now in early clinical trials, and the diaziridinyl-benzoquinone methyl-DZQ, which has been selected very recently for clinical development. The complex interplay of the levels of oxygen and of DT-diaphorase governs the effectiveness of these agents and other quinones such as mitomycin C. A model is proposed to account for the behaviour observed. Advantages and disadvantages of the enzyme-directed bioreductive approach are summarised and future prospects are critically assessed.