PMID: 7536024Apr 1, 1995Paper

Indoloquinone EO9: DNA interstrand cross-linking upon reduction by DT-diaphorase or xanthine oxidase

British Journal of Cancer
M MaliepaardL H Janssen

Abstract

We report DNA interstrand cross-linking caused by the anti-tumour indoloquinone EO9 following reductive activation with purified rat liver DT-diaphorase or xanthine oxidase. Reduction was a necessary event for cross-linking to occur. DNA cross-link formation by EO9 following DT-diaphorase reduction was completely inhibited by addition 10 microM dicoumarol, whereas only a minor effect of dicoumarol on xanthine oxidase-mediated DNA cross-linking by EO9 was observed. DNA cross-linking was pH dependent, with increasing cross-link formation from pH 5.5 to 7.0 for both DT-diaphorase and xanthine oxidase mediated reactions. Also, conversion of EO9 upon reduction was pH dependent. However, in contrast to DNA cross-linking, conversion rates of EO9 decreased at higher pH. EO9 was shown to be more efficient in DNA cross-linking than mitomycin C under identical conditions, using both DT-diaphorase and xanthine oxidase reductive activation at pH 5.5 and 7.0. This study indicates that the anti-tumour activity of EO9 may be at least partly mediated by interstrand DNA cross-link formation, and that various reducing enzymes may be important for activation of EO9 in vitro and in vivo.

Citations

Sep 23, 2003·Anti-cancer Drugs·Angela M Di FrancescoMoses Lee
Apr 19, 2012·British Journal of Pharmacology·Roger M PhillipsUNKNOWN EORTC-Pharmacology and Molecular Mechanism Group
Jun 24, 2017·Expert Opinion on Drug Metabolism & Toxicology·R M PhillipsG J Peters
Nov 16, 2007·Organic & Biomolecular Chemistry·Kazuhito TanabeSei-ichi Nishimoto
Jul 5, 2005·Expert Opinion on Investigational Drugs·R M Phillips
Jun 14, 2008·Expert Opinion on Investigational Drugs·J Alfred Witjes, Prasad S Kolli
Aug 1, 1996·Free Radical Research·J ButlerJ Cummings
Apr 1, 1996·General Pharmacology·E Smitskamp-WilmsG J Peters
Sep 18, 2007·European Journal of Medicinal Chemistry·Philip ReiganSally Freeman

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