IMR Press / FBL / Volume 5 / Issue 3 / DOI: 10.2741/beall

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.

Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development
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1 Department of Pharmaceutical Sciences, School of Pharmacy, The University of Montana, Missoula, MT 59812, USA
2 Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
Front. Biosci. (Landmark Ed) 2000, 5(3), 639–648;
Published: 1 July 2000

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

NAD(P)H:quinone oxidoreductase
Antitumor quinones
Alkylating agents
Mitomycin C
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