Hazlehurst L A, Krapcho A P, Hacker M P
Department of Pharmacology, University of Vermont College of Medicine, Burlington, USA.
Biochem Pharmacol. 1995 Sep 28;50(7):1087-94. doi: 10.1016/0006-2952(95)00246-v.
Aza-anthracenediones are a new class of anti-cancer drugs, which demonstrate promising in vitro and in vivo activity. Our laboratory has synthesized a variety of structural analogs in which we determined previously that the positioning of the nitrogen within the backbone, as well as sidearm modification, results in dramatic differences in the potency of cytotoxicity. We reported previously that although DNA reactivity appears to be a necessary component for mediating cell death, it is not sufficient for predicting cytotoxicity of the aza-anthracenediones. We have chosen three aza-anthracenediones (BBR 2828, BBR 2778 and BBR 2378) to investigate the importance of DNA strand breaks and/or protein-concealed DNA breaks induced by aza-anthracenediones. We determined in the present study that, while all three drugs cause DNA breaks as determined by alkaline and neutral elution, as well as KCl-SDS precipitation, these breaks do not correlate directly with their potency as cytotoxic compounds. Further, we found significant differences in the types of DNA breaks induced by these drugs. Finally, we report that the persistence of protein-DNA complexes induced by all three drugs was similar and, therefore, cannot account for differences in the potency of cytotoxicity of the aza-anthracenediones. Thus, we postulate that, while the total number of drug-induced protein-concealed DNA breaks is an important indicator of drug toxicity, it is possible that the actual nature of the breaks may differ among the aza-anthracenedione congeners, and it is these differences in the actual proteins present in the DNA breaks that differentiate between aza-anthracenediones.
氮杂蒽二酮是一类新型抗癌药物，在体外和体内均显示出有前景的活性。我们实验室已合成了多种结构类似物，此前我们确定了主链中氮的位置以及侧链修饰会导致细胞毒性效力的显著差异。我们先前报道过，尽管DNA反应性似乎是介导细胞死亡的必要组成部分，但它不足以预测氮杂蒽二酮的细胞毒性。我们选择了三种氮杂蒽二酮（BBR 2828、BBR 2778和BBR 2378）来研究氮杂蒽二酮诱导的DNA链断裂和/或蛋白质掩盖的DNA断裂的重要性。我们在本研究中确定，虽然通过碱性和中性洗脱以及KCl-SDS沉淀测定，所有这三种药物都会导致DNA断裂，但这些断裂与它们作为细胞毒性化合物的效力并不直接相关。此外，我们发现这些药物诱导的DNA断裂类型存在显著差异。最后，我们报道所有这三种药物诱导的蛋白质-DNA复合物的持久性相似，因此不能解释氮杂蒽二酮细胞毒性效力的差异。因此，我们推测，虽然药物诱导的蛋白质掩盖的DNA断裂总数是药物毒性的重要指标，但氮杂蒽二酮同系物之间断裂的实际性质可能不同，正是DNA断裂中存在的实际蛋白质的这些差异区分了氮杂蒽二酮。
