Malina Jaroslav, Natile Giovanni, Brabec Viktor
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i. Kralovopolska 135, 61265 Brno (Czech Republic), Fax: (+420) 541240499.
Chemistry. 2013 Sep 2;19(36):11984-91. doi: 10.1002/chem.201300946. Epub 2013 Jul 19.
Oxaliplatin and cisplatin belong to the class of platinum-based anticancer agents. Formation of DNA adducts by these complexes and the consequences for its structure and function, is the mechanistic paradigm by which these drugs exert their antitumor activity. We show that employing short oligonucleotide duplexes containing single, site-specific 1,3-intrastrand cross-links of oxaliplatin, its enantiomeric analogue, or cisplatin and by using gel electrophoresis that under physiological conditions the coordination bonds between platinum and the N7 position of guanine residues involved in the cross-links of the Pt(II) complexes can be cleaved. This cleavage may lead to linkage isomerization reactions between these metallodrugs and double-helical DNA. For instance, approximately 25 % 1,3-intrastrand cross-links of the platinum complexes isomerized after 192 h (at 310 K in 200 mM NaClO4). Differential scanning calorimetry of duplexes containing single, site-specific cross-links of oxaliplatin, its enantiomeric analogue, and cisplatin reveals that one of the driving forces that leads to the lability of DNA cross-links of these metallodrugs is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of the DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule. In addition, the differences in the kinetics of the rearrangement reactions and the thermodynamic destabilization of DNA observed for adducts of oxaliplatin and its enantiomeric analogue confirm that the chirality at the carrier 1,2-diaminocyclohexane ligand can considerably affect structural and other physical properties of DNA adducts and consequently their biological effects. In aggregate, interesting generalization of the results described in this work might be that the migration of oxaliplatin, its enantiomeric analogue, or cisplatin from one strand to another in double-helical DNA controlled by energetic signatures of these agents might contribute to a better understanding of their cytotoxic and mutagenic potential.
奥沙利铂和顺铂属于铂类抗癌药物。这些配合物形成DNA加合物及其对DNA结构和功能的影响，是这些药物发挥抗肿瘤活性的作用机制范例。我们发现，使用含有奥沙利铂、其对映体类似物或顺铂的单个位点特异性1,3-链内交联的短寡核苷酸双链体，并通过凝胶电泳表明，在生理条件下，铂与参与Pt(II)配合物交联的鸟嘌呤残基N7位置之间的配位键可以被裂解。这种裂解可能导致这些金属药物与双螺旋DNA之间发生连接异构化反应。例如，铂配合物约25%的1,3-链内交联在192小时后（在310K、200mM高氯酸钠中）发生异构化。对含有奥沙利铂、其对映体类似物和顺铂的单个位点特异性交联的双链体进行差示扫描量热法分析表明，导致这些金属药物DNA交联不稳定的驱动力之一是交联和其可能异构化形成的加合物所引起的热力学不稳定之间的差异。重排可能以这样的方式进行：最初在DNA一条链中形成的交联可以自发地从一条DNA链转移到其互补链，这可能引发铂配合物在DNA分子上移动。此外，奥沙利铂及其对映体类似物加合物的重排反应动力学差异以及DNA的热力学不稳定证实，载体1,2-二氨基环己烷配体的手性可显著影响DNA加合物的结构和其他物理性质，进而影响其生物学效应。总的来说，这项工作中描述的结果有趣的概括可能是，奥沙利铂、其对映体类似物或顺铂在双螺旋DNA中从一条链迁移到另一条链受这些药物能量特征的控制，这可能有助于更好地理解它们的细胞毒性和诱变潜力。
