Jennerwein M M, Eastman A, Khokhar A
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68105.
Chem Biol Interact. 1989;70(1-2):39-49. doi: 10.1016/0009-2797(89)90061-6.
The cancer chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-DDP) is active as a result of its bifunctional reactions with DNA. Many other platinum complexes also have therapeutic activity. Of current interest are complexes containing 1,2-diaminocyclohexane (DACH). The DACH ligand exists in three isomeric forms with reported differences in therapeutic activity in the order R,R greater than S,S greater than R,S-DACH-Pt. The reaction of the sulphate form of each of these three isomers with DNA has been characterized as a possible explanation for the apparent differences in antitumor activity. These reactions have been characterized by platinating pure DNA followed by enzyme digestion, HPLC separation and analysis by atomic absorption and nuclear magnetic resonance. The spectrum of adducts produced was similar for each isomer and similar to that reported for cis-DDP with adduction at d(GpG), d(ApG) and (dG)2. The R,S-isomer additionally demonstrated isomeric adducts at d(GpG) and d(ApG). The kinetics of formation of the various adducts was the same for each isomer; total platination of DNA was complete in 15 min as were bifunctional adducts at d(GpG) and (dG)2. However, rearrangement to bifunctional adducts took several hours in the case of adducts at d(ApG) sequences. These results did not provide a reason for the different activities of the isomers. It is suggested that the interaction of these adducts with metabolic processes such as DNA repair might explain these differences.
癌症化疗药物顺二氨二氯铂（II）（顺铂）因其与DNA的双功能反应而具有活性。许多其他铂配合物也具有治疗活性。目前人们感兴趣的是含有1,2 - 二氨基环己烷（DACH）的配合物。DACH配体以三种异构体形式存在，据报道其治疗活性存在差异，顺序为R,R大于S,S大于R,S - DACH - Pt。这三种异构体的硫酸盐形式与DNA的反应已得到表征，以此作为解释其抗肿瘤活性明显差异的一种可能原因。这些反应通过用铂处理纯DNA，然后进行酶消化、高效液相色谱分离以及原子吸收和核磁共振分析来表征。每种异构体产生的加合物谱相似，且与报道的顺铂在d（GpG）、d（ApG）和（dG）2处的加合物谱相似。R,S - 异构体在d（GpG）和d（ApG）处还显示出异构体加合物。每种异构体形成各种加合物的动力学相同；DNA的完全铂化在15分钟内完成，d（GpG）和（dG）2处的双功能加合物也是如此。然而，对于d（ApG）序列处的加合物，重排为双功能加合物需要数小时。这些结果并未为异构体的不同活性提供原因。有人认为这些加合物与DNA修复等代谢过程的相互作用可能解释了这些差异。
