Mechanisms of action of quinone-containing alkylating agents I: NQO1-directed drug development

Alkylating agents have been used to treat cancer since the 1940s. Quinone-c ontaining alkylating agents represent a class of drugs called "bioreductive alkylating agents." These drugs require reduction of the quinone moiety fo r activation of their alkylating substituents. Despite active research in t his area, mitomycin C is the only bioreductive alkylating agent approved fo r general use. The "enzyme-directed" approach to bioreductive drug developm ent involves identification of reductases which are overexpressed in tumors when compared to uninvolved tissues. Bioreductive drugs which are substrat es for these reductases should be selectively toxic to tumors with high red uctase levels. NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase, EC 1.6. 99.2) is a two-electron reductase found primarily in the cytosol. NQO1 has received considerable attention because of the high levels of this enzyme i n tumors particularly in tumors of the lung, colon and breast. In this revi ew, the current state of research on quinone-containing alkylating agents i s discussed with the focus on NQO1-directed bioreductive drug development. Recent structure-activity studies on indolequinones, benzoquinones and othe r novel quinones are reviewed, and the status of drugs which have been stud ied in clinical trials is discussed. Finally, the limitations and possible future directions in this research area are presented.