Begleiter A, Robotham E, Lacey G, Leith M K
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Cancer Lett. 1989 Jun;45(3):173-6. doi: 10.1016/0304-3835(89)90073-6.
L5178Y cells resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard, were four-fold more sensitive to mitomycin C compared to parental cells. Mitomycin C also produced increased DNA-DNA crosslinking in these cells compared to parental L5178Y cells, but did not induce DNA double strand breaks in either cell line. The resistant cells have a 24-fold increased level of DT-diaphorase activity, an enzyme that produces two electron reduction of quinone groups. Dicoumarol, an inhibitor of DT-diaphorase, significantly inhibited crosslinking and cytotoxicity by mitomycin C in the quinone resistant cells. These findings suggest that DNA-DNA cross-linking may be a major contributor to mitomycin C cytotoxic activity in L5178Y cells, and that the hydroquinone of mitomycin C may play a major role in the crosslinking activity of this agent.
对模型醌类抗肿瘤药物水解苯醌氮芥具有抗性的L5178Y细胞，与亲代细胞相比，对丝裂霉素C的敏感性高四倍。与亲代L5178Y细胞相比，丝裂霉素C在这些细胞中也产生了更多的DNA-DNA交联，但在两种细胞系中均未诱导DNA双链断裂。抗性细胞中DT-黄递酶活性水平增加了24倍，DT-黄递酶是一种能使醌基团发生双电子还原的酶。双香豆素是DT-黄递酶的抑制剂，它能显著抑制醌抗性细胞中丝裂霉素C的交联作用和细胞毒性。这些发现表明，DNA-DNA交联可能是丝裂霉素C在L5178Y细胞中细胞毒性活性的主要贡献因素，并且丝裂霉素C的对苯二酚可能在该药物的交联活性中起主要作用。
