Zákovská A, Nováková O, Balcarová Z, Bierbach U, Farrell N, Brabec V
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno.
Eur J Biochem. 1998 Jun 15;254(3):547-57. doi: 10.1046/j.1432-1327.1998.2540547.x.
Recent observations that several trans-platinum complexes exhibit antitumor activity including activity in cisplatin-resistant tumor cells, violates the classical structure/activity relationships of platinum(II) complexes. According to these relationships, only bifunctional platinum(II) complexes with cis-oriented leaving ligands should be therapeutically active. In order to contribute to the understanding of mechanisms underlying the antitumor activity of these new trans-platinum analogs, various biochemical and biophysical methods as well as molecular modeling techniques were employed to study the modifications of DNA by antitumor trans-[PtCl2(NH3)(quinoline)]. The results indicated that trans-[PtCl2(NH3)(quinoline)] coordinated monofunctionally to DNA with a similar rate as transplatin. The overall rate of the rearrangement to bifunctional adducts was also similar to that observed in the case of DNA modification by transplatin, i.e. it was relatively slow (after 48 h approximately 34% adducts remained monofunctional). In contrast to transplatin, however, trans-[PtCl2(NH3)(quinoline)] formed considerably more interstrand cross-links after 48 h (approximately 30%) with a much shorter half-time (approximately 5 h) (approximately 12% for transplatin, t1/2 > 11 h). The results also suggested that the quinoline ligand in all or in a significant fraction of DNA adducts of trans-[PtCl2(NH3)(quinoline)], in which platinum is coordinated to base residues, was well positioned to interact with the duplex. The adducts of trans-[PtCl2(NH3)(quinoline)] terminated in vitro RNA synthesis preferentially at guanine residues. Surprisingly, the type and extent of conformational alterations induced in DNA indicates that trans-[PtCl2(NH3)(quinoline)] behaves in some respects like cisplatin, as indicated by the fact that trans-[PtCl2(NH3)(quinoline)]-modified DNA is recognized by cisplatin-specific antibodies. Models for both monofunctional adducts and bifunctional interstrand cross-links are proposed. Computer-generated AMBER models show that the combination of monofunctional covalent binding and a stacking interaction between quinoline and the DNA bases can produce a kink in the duplex which is strongly suggestive of the directed bend produced by the major cisplatin-DNA adduct (1,2 intrastrand cross-link). Unique DNA adducts of this type formed by trans-[PtCl2(NH3)(quinoline)] may contribute to the antitumor efficacy of this agent.
最近的观察结果表明，几种反式铂配合物具有抗肿瘤活性，包括对顺铂耐药肿瘤细胞的活性，这违背了铂（II）配合物的经典结构/活性关系。根据这些关系，只有具有顺式取向离去配体的双功能铂（II）配合物才应具有治疗活性。为了有助于理解这些新型反式铂类似物抗肿瘤活性的潜在机制，采用了各种生化和生物物理方法以及分子建模技术来研究抗肿瘤反式-[PtCl2(NH3)(喹啉)]对DNA的修饰作用。结果表明，反式-[PtCl2(NH3)(喹啉)]以与反式铂相似的速率单功能地与DNA配位。重排为双功能加合物的总体速率也与反式铂修饰DNA时观察到的速率相似，即相对较慢（48小时后约34%的加合物仍为单功能）。然而，与反式铂不同的是，反式-[PtCl2(NH3)(喹啉)]在48小时后形成的链间交联明显更多（约30%），半衰期短得多（约5小时）（反式铂为约12%，t1/2>11小时）。结果还表明，在反式-[PtCl2(NH3)(喹啉)]的所有或大部分DNA加合物中，喹啉配体在铂与碱基残基配位的情况下，位置良好，可与双链相互作用。反式-[PtCl2(NH3)(喹啉)]的加合物在体外RNA合成中优先在鸟嘌呤残基处终止。令人惊讶的是，DNA中诱导的构象改变的类型和程度表明，反式-[PtCl2(NH3)(喹啉)]在某些方面的行为类似于顺铂，这一事实表明反式-[PtCl2(NH3)(喹啉)]修饰的DNA能被顺铂特异性抗体识别。提出了单功能加合物和双功能链间交联的模型。计算机生成的AMBER模型表明，单功能共价结合以及喹啉与DNA碱基之间的堆积相互作用相结合，可以在双链中产生一个扭结，这强烈暗示了主要顺铂-DNA加合物（1,2链内交联）产生的定向弯曲。反式-[PtCl2(NH3)(喹啉)]形成的这种独特的DNA加合物可能有助于该药物的抗肿瘤疗效。
