Esnault C, Brown S C, Segal-Bendirdjian E, Coulaud D, Mishal Z, Roques B P, Le Pecq J B
Unite de Physiocochimie Macromoleculaire (CNRS UA158, INSERM U140) Institut Gustave Roussy, Villejuif, France.
Biochem Pharmacol. 1990 Jan 1;39(1):109-22. doi: 10.1016/0006-2952(90)90654-4.
The bifunctional intercalator Ditercalinium (NSC 335153) demonstrates an anti-tumoral cytotoxicity markedly different from other intercalating agents. A delayed toxicity is observed in eucaryotic cells, both in vitro and in vivo, at drug concentrations far below those required to observe immediate toxic effects. Fluorescence microscopy demonstrates that Ditercalinium and the mitochondrial-staining fluorophore DiOC2(5) are concentrated in the same cellular organelles of L1210 cells. Electron microscopy of Ditercalinium-treated cells reveals extensive and progressive swelling of mitochondria, with no other ultrastructural changes observed. Ditercalinium uptake and toxicity are in part related to mitochondrial membrane potential. However, drug accumulation itself does not immediately alter the mitochondrial membrane potential. Cellular ATP pool levels and the rate of respiration fall progressively after drug treatment. Nucleotide pools in DC3F cells, measured between drug treatment and death, show marked drops in pyrimidine levels while purine nucleotide levels decline more slowly. Addition of uridine or cytidine partially rescues Ditercalinium-treated cells, while toxicity is increased in the presence of 2-deoxyglucose. The combined evidence indicates that the toxicity of Ditercalinium to murine leukemia cells (L1210) and Chinese Hamster lung cells (DC3F) is due to disruption of mitochondrial function.
双功能嵌入剂二萜卡铵（NSC 335153）表现出与其他嵌入剂明显不同的抗肿瘤细胞毒性。在真核细胞中，无论是体外还是体内，在远低于观察到即时毒性作用所需浓度的药物浓度下，都会观察到延迟毒性。荧光显微镜检查表明，二萜卡铵和线粒体染色荧光团DiOC2(5)集中在L1210细胞的相同细胞器中。对经二萜卡铵处理的细胞进行电子显微镜检查发现线粒体广泛且逐渐肿胀，未观察到其他超微结构变化。二萜卡铵的摄取和毒性部分与线粒体膜电位有关。然而，药物积累本身并不会立即改变线粒体膜电位。药物处理后，细胞ATP池水平和呼吸速率逐渐下降。在药物处理至细胞死亡期间测量的DC3F细胞中的核苷酸池显示嘧啶水平显著下降，而嘌呤核苷酸水平下降较慢。添加尿苷或胞苷可部分挽救经二萜卡铵处理的细胞，而在2-脱氧葡萄糖存在下毒性会增加。综合证据表明，二萜卡铵对小鼠白血病细胞（L1210）和中国仓鼠肺细胞（DC3F）的毒性是由于线粒体功能的破坏。
