Begleiter A, Blair G W
Cancer Res. 1984 Jan;44(1):78-82.
The presence of a quinone group in the structure of a series of model compounds was shown to produce cell kill by a mechanism involving free radicals and active oxygen species. Furthermore, the ability of the compound to bind to DNA appeared to enhance its cytocidal activity. The same model compounds were used to investigate the effect of the quinone group on cellular DNA. DNA single-strand breaks, DNA double-strand breaks, and DNA-DNA cross-linking induced by the model compounds were measured by elution assays. Hydrolyzed benzoquinone mustard, which contains a quinone group, induced dose-dependent single-strand and double-strand breaks but no DNA cross-linking. Benzoquinone 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. However, 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 approximately 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. These studies provided evidence that 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.
一系列模型化合物结构中醌基团的存在表明，其通过涉及自由基和活性氧物种的机制导致细胞死亡。此外，该化合物与DNA结合的能力似乎增强了其杀细胞活性。相同的模型化合物被用于研究醌基团对细胞DNA的影响。通过洗脱测定法测量模型化合物诱导的DNA单链断裂、双链断裂和DNA-DNA交联。含有醌基团的水解苯醌氮芥诱导剂量依赖性的单链和双链断裂，但不诱导DNA交联。同时具有醌部分和活性烷基化基团的苯醌氮芥产生剂量依赖性的DNA双链断裂，但无明显的单链断裂。然而，该化合物产生了显著水平的DNA交联，这一过程干扰了单链断裂的测定。苯醌氮芥诱导DNA双链断裂的相对活性比水解苯醌氮芥大约高15000倍。与苯醌氮芥具有相同烷基化基团但无醌功能的苯胺氮芥产生较低水平的DNA-DNA交联，且不产生DNA链断裂。细胞保护酶超氧化物歧化酶和过氧化氢酶显著抑制了水解苯醌氮芥诱导的DNA单链和双链断裂。水解苯醌氮芥的细胞毒性活性似乎与DNA单链和双链断裂的诱导相关。这些研究提供了证据，表明化合物化学结构中醌基团的存在导致DNA链断裂。超氧化物歧化酶和过氧化氢酶抑制了DNA损伤，表明自由基和活性氧物种的参与。化合物与DNA结合的能力似乎增强了DNA损伤的诱导。链断裂的诱导可能与醌类药物的细胞毒性活性相关。
