QUINONE-INDUCED DNA DAMAGE AND ITS RELATIONSHIP TO ANTITUMOR-ACTIVITY IN L5178Y LYMPHOBLASTS

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (1) , 78-82
Abstract
The presence of a quinone group in the structure of a series of model compounds produced cell kill by a mechanism involving free radicals and active oxygen species. The ability of the compound to bind to DNA appeared to enhance its cytocidal activity [in mouse leukemia L5178Y cells]. The same model compounds were used to investigate the effect of the quinone group on cellular DNA. DNA single-stranded breaks, DNA double-stranded breaks and DNA-DNA cross-linking induced by the model compounds were measured by elution assays. Hydrolyzed benzoquione mustard, which contains a quinone group, induced dose-dependent single-strand and double-strand breaks but no DNA cross-linking. Benzoquionine mustard, which possesses both a quinone moiety and an active alkylating group, produced dose-dependent DNA double-strand breaks but no apparent single-strand breaks. This compound produced significant levels of DNA cross-linking, a process which interferes with the assay for single-strand breaks. The relative activity of benzoquinone mustard in inducing DNA double-strand breaks was .apprx. 15,000-fold greater than that of hydrolyzed benzoquinone mustard. Aniline mustard, which has the same alkylating group as does benzoquinone mustard but no quinone function, produced lower levels of DNA-DNA cross-links and no DNA strand breaks. The induction of both DNA single-strand and double-strand breaks by hydrolyzed benzoquinone mustard was significantly inhibited by the cell-protective enzymes superoxide dismutase and catalase. The cytotoxic activity of hydrolyzed benzoquinone mustard appeared to correlate with the induction of DNA single- and double-strand breaks. The presence of a quinone group in the chemical structure of a compound results in the production of DNA strand breaks. DNA damage was inhibited by superoxide dismutase and catalase, suggesting the involvement of free radicals and active oxygen species. The induction of DNA damage appeared to be enhanced by the ability of the compound to bind to DNA. The induction of strand breaks may correlate with the cytotoxic activity of the quinone agents.