Andrivon W, Saucier J M, Auclair C, Monneret C, Florent J C, Guillosson J J, Nafziger J
Laboratoire d'Hématologie Cellulaire et Moléculaire, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Leuk Res. 1996 Feb;20(2):119-26. doi: 10.1016/0145-2126(95)00155-7.
In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.
在先前的一项研究中，我们报道了一种新的蒽环类衍生物（莫弗洛霉素）与其他蒽环类药物（如柔红霉素和阿霉素）相比，具有更高的抗白血病活性。为了解释莫弗洛霉素的优越抗白血病作用并揭示可能的构效关系，我们研究了蒽环类药物发挥抗肿瘤作用的三种主要机制：DNA结合、自由基产生和拓扑异构酶II抑制。通过DNA结合和DNA解旋试验评估DNA相互作用，通过电子自旋共振研究自由基生成，通过分析酶诱导的DNA断裂刺激来研究拓扑异构酶II相互作用。结果表明，与阿霉素相比，莫弗洛霉素产生的自由基更多，对拓扑异构酶II介导的DNA切割的刺激更大，且与较低的DNA亲和力相关。莫弗洛霉素的不同生化特性，特别是其与拓扑异构酶II的相互作用，与发色团上进行的结构修饰有关。这些特性，再加上糖部分存在碘原子导致分子具有更高的稳定性，可能是该化合物具有更高抗白血病活性的原因。
