title: Studies on the mechanism of action of quinone antitumor agents.
abstract: The presence of a quinone group in the structure of a compound has been shown to produce cell kill and DNA strand breaks by a mechanism involving free radicals and active oxygen species. The ability of the compound to bind to DNA appeared to increase the DNA damage induced and the cytotoxic activity. A new series of model compounds has been used to investigate further the role of the quinone group in the mechanism of action of quinone antitumor agents. Bis(dimethylamino)benzoquinone, which contains a quinone group, produced significant cell kill of L5178Y lymphoblasts and induced concentration-dependent single-strand and double-strand breaks in the DNA of these cells. Benzoquinone dimustard, which possesses a quinone moiety and active alkylating groups, was approximately 2500 times more cycotoxic to L5178Y cells than was bis(dimethylamino)benzoquinone and was approximately 200-fold more active in inducing DNA double-strand breaks than was the quinone agent. Benzoquinone dimustard induced no apparent DNA single-strand breaks, but produced significant DNA cross-linking, a process which interferes with the assay for single-strand breaks. The cell kill produced by both quinone agents was inhibited by catalase, but not by superoxide dismutase. The cytotoxic activity of bis(dimethylamino)benzoquinone and two other quinone model compounds, hydrolyzed benzoquinone mustard and benzoquinone mustard, appeared to correlate with the induction of DNA strand breaks, while there appeared to be no correlation between cell kill and DNA double-strand breaks induced by benzoquinone dimustard. However, the cytotoxicity of benzoquinone dimustard appeared to be related to the cross-linking activity of this agent. These studies have provided additional evidence that the presence of a quinone group in the structure of a compound can result in significant cell kill by a mechanism that appears to involve active oxygen species. Quinone containing agents can induce DNA strand breaks, and this effect is enhanced when the agent is able to bind to DNA. The induction of DNA strand breaks appeared to correlate with cytotoxic activity for bis(dimethylamino)benzoquinone, hydrolyzed benzoquinone mustard and benzoquinone mustard, but not for benzoquinone dimustard, suggesting that the contribution of quinone-induced strand breaks to the overall cytotoxicity of an agent may vary considerably.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D004247:DNA; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D009588:Nitrogen Mustard Compounds; D011809:Quinones; C046023:2,5-bis(dimethylamino)-1,4-benzoquinone; C046024:1,4-benzoquinone-2,5-dimustard; C040042:2-(bis(2-chloroethyl)amino)-1,4-benzoquinone; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase