Begleiter A, Leith M K
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Cancer Res. 1990 May 15;50(10):2872-6.
The role of the quinone group in the antitumor activity of quinone alkylating agents, such as mitomycin C and 2,5-diaziridinyl-3,5-bis(carboethoxyamino)-1,4-benzoquinone, is still uncertain. The quinone group may contribute to antitumor activity by inducing DNA strand breaks through the formation of free radicals and/or by influencing the alkylating activity of the quinone alkylators. The cytotoxic activity and DNA damage produced by the model quinone alkylating agents, benzoquinone mustard and benzoquinone dimustard, were compared in L5178Y murine lymphoblasts sensitive and resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, have increased concentrations of glutathione and elevated catalase, superoxide dismutase, glutathione S-transferase, and DT-diaphorase activity. L5178Y/HBM2 and L5178Y/HBM10 cells were 7.4- and 8.5-fold less sensitive to benzoquinone mustard and 1.7- and 4.3-fold less sensitive to benzoquinone dimustard, respectively, compared with sensitive cells, but showed no resistance to the non-quinone alkylating agent, aniline mustard. The formation of DNA double strand breaks by benzoquinone mustard was reduced by 2- and 8-fold in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, while double strand break formation by benzoquinone dimustard was reduced only in the L5178Y/HBM10 cells. The number of DNA-DNA cross-links produced by benzoquinone mustard was 3- and 6-fold lower, and the number produced by benzoquinone dimustard was 35% and 2-fold lower in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared with L5178Y parental cells. In contrast, cross-linking by aniline mustard was unchanged in sensitive and resistant cells. Dicoumarol, an inhibitor of DT-diaphorase, increased the cytotoxic activity of both benzoquinone mustard and benzoquinone dimustard in L5178Y/HBM10 cells. This study provides evidence that elevated DT-diaphorase activity in the resistant cells contributes to resistance to benzoquinone mustard and benzoquinone dimustard, possibly by decreasing the formation of the semiquinone intermediates of these agents. The altered reduction of the quinone groups in the resistant cells may be responsible for the decreased DNA-DNA cross-linking and lowered induction of DNA strand breaks by the quinone alkylating agents. These findings demonstrate that the quinone group can modulate the activity of quinone alkylating agents. The study also suggests that the semiquinone intermediates of benzoquinone mustard and benzoquinone dimustard may be the active alkylating species of these two agents.
醌基在醌类烷基化剂（如丝裂霉素C和2,5-二氮丙啶基-3,5-双（乙氧羰基氨基）-1,4-苯醌）的抗肿瘤活性中的作用仍不确定。醌基可能通过形成自由基诱导DNA链断裂和/或通过影响醌类烷基化剂的烷基化活性来促进抗肿瘤活性。在对模型醌类抗肿瘤剂水解苯醌芥敏感和耐药的L5178Y小鼠成淋巴细胞中，比较了模型醌类烷基化剂苯醌芥和苯醌二芥产生的细胞毒性活性和DNA损伤。耐药细胞系L5178Y/HBM2和L5178Y/HBM10的谷胱甘肽浓度增加，过氧化氢酶、超氧化物歧化酶、谷胱甘肽S-转移酶和DT-黄递酶活性升高。与敏感细胞相比，L5178Y/HBM2和L5178Y/HBM10细胞对苯醌芥的敏感性分别降低了7.4倍和8.5倍，对苯醌二芥的敏感性分别降低了1.7倍和4.3倍，但对非醌类烷基化剂苯胺芥没有耐药性。在L5178Y/HBM2和L5178Y/HBM10细胞中，苯醌芥诱导的DNA双链断裂分别减少了2倍和8倍，而苯醌二芥诱导的双链断裂仅在L5178Y/HBM10细胞中减少。与L5178Y亲本细胞相比，L5178Y/HBM2和L5178Y/HBM10细胞中苯醌芥产生的DNA-DNA交联数量分别降低了3倍和6倍，苯醌二芥产生的交联数量分别降低了35%和2倍。相比之下，苯胺芥在敏感和耐药细胞中的交联没有变化。DT-黄递酶抑制剂双香豆素增加了L5178Y/HBM10细胞中苯醌芥和苯醌二芥的细胞毒性活性。这项研究提供了证据，表明耐药细胞中升高的DT-黄递酶活性可能通过减少这些药物的半醌中间体的形成，导致对苯醌芥和苯醌二芥的耐药性。耐药细胞中醌基还原的改变可能是醌类烷基化剂导致DNA-DNA交联减少和DNA链断裂诱导降低的原因。这些发现表明醌基可以调节醌类烷基化剂的活性。该研究还表明，苯醌芥和苯醌二芥的半醌中间体可能是这两种药物的活性烷基化物种。
