Begleiter A
Biochem Pharmacol. 1985 Aug 1;34(15):2629-36. doi: 10.1016/0006-2952(85)90559-3.
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.
化合物结构中醌基团的存在已表明，其通过涉及自由基和活性氧物种的机制导致细胞死亡和DNA链断裂。该化合物与DNA结合的能力似乎会增加诱导的DNA损伤和细胞毒性活性。一系列新的模型化合物已被用于进一步研究醌基团在醌类抗肿瘤药物作用机制中的作用。含有醌基团的双（二甲基氨基）苯醌对L5178Y成淋巴细胞产生显著的细胞杀伤作用，并在这些细胞的DNA中诱导浓度依赖性的单链和双链断裂。具有醌部分和活性烷基化基团的苯醌二氮芥对L5178Y细胞的细胞毒性比双（二甲基氨基）苯醌大约高2500倍，并且在诱导DNA双链断裂方面的活性比醌类药物大约高200倍。苯醌二氮芥未诱导明显的DNA单链断裂，但产生显著的DNA交联，这一过程会干扰单链断裂的检测。两种醌类药物产生的细胞杀伤作用均受到过氧化氢酶的抑制，但不受超氧化物歧化酶的抑制。双（二甲基氨基）苯醌以及另外两种醌类模型化合物水解苯醌氮芥和苯醌氮芥的细胞毒性活性似乎与DNA链断裂的诱导相关，而苯醌二氮芥诱导的细胞杀伤与DNA双链断裂之间似乎没有相关性。然而，苯醌二氮芥的细胞毒性似乎与其交联活性有关。这些研究提供了额外的证据，表明化合物结构中醌基团的存在可通过一种似乎涉及活性氧物种的机制导致显著的细胞死亡。含醌药物可诱导DNA链断裂，当该药物能够与DNA结合时，这种作用会增强。对于双（二甲基氨基）苯醌、水解苯醌氮芥和苯醌氮芥，DNA链断裂的诱导似乎与细胞毒性活性相关，但对于苯醌二氮芥则不然，这表明醌诱导的链断裂对药物整体细胞毒性的贡献可能有很大差异。
