Boccarelli Angelina, Giordano Domenico, Natile Giovanni, Coluccia Mauro
Department Biomedical Sciences and Human Oncology, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy.
Biochem Pharmacol. 2006 Jul 28;72(3):280-92. doi: 10.1016/j.bcp.2006.04.021. Epub 2006 May 1.
In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.
为了比较抗肿瘤活性反式铂配合物反式-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))]（反式-Z）和顺铂的抗肿瘤无活性异构体反式-[PtCl(2)(NH(3))(2)]（反式-DDP）的作用机制特性，研究了SKOV-3卵巢癌细胞对这两种化合物的差异处理。反式-Z和反式-DDP以相同的效率进入细胞，但反式-Z对细胞DNA的亲和力高两倍。用反式-DDP的半数抑制浓度（IC(50)）处理会产生初始的、短暂的细胞生长抑制作用，同时伴随着凋亡适度增加以及细胞周期的S期和G(2)/M期的顺序性和可逆性阻滞。相比之下，反式-Z的IC(50)会产生初始的细胞毒性作用、更持久且显著的凋亡增加以及细胞周期的S期和G(2)/M期更显著且持久的阻滞。治疗诱导的基因表达变化表明，反式-DDP的表型效应是由一些与细胞周期检查点和阻滞网络相关的基因的初始和短暂上调驱动的，而反式-Z更显著的表型效应是由更多参与细胞周期检查点和阻滞网络、基因组稳定性和DNA修复的基因的持续上调驱动的。因此，已经确定了由反式-Z而非反式-DDP产生的分子和细胞事件，这些事件可能代表了反式-Z在SKOV-3系统中抗肿瘤活性的作用机制基础。
