INVIVO EFFECTS OF CIS-DIAMMINEDICHLOROPLATINUM(II) AND TRANS-DIAMMINEDICHLOROPLATINUM(II) ON SV40 CHROMOSOMES - DIFFERENTIAL REPAIR, DNA PROTEIN CROSS-LINKING, AND INHIBITION OF REPLICATION
INVIVO EFFECTS OF CIS-DIAMMINEDICHLOROPLATINUM(II) AND TRANS-DIAMMINEDICHLOROPLATINUM(II) ON SV40 CHROMOSOMES - DIFFERENTIAL REPAIR, DNA PROTEIN CROSS-LINKING, AND INHIBITION OF REPLICATION
复制标题
DOI：
10.1021/bi00347a005
复制
发表时间：
1985-12-17
期刊：
影响因子：
2.9
通讯作者：
LIPPARD, SJ
中科院分区：
文献类型：
--
作者：
CICCARELLI, RB;SOLOMON, MJ;LIPPARD, SJ
本文用高效液相色谱法研究了抗肿瘤药物顺-二氨二氯铂（Ⅱ）（cis-DDP）的作用机理。5200碱基对（bp）的猿猴病毒40（SV 40）染色体作为体内染色质模型。还对临床无效的异构体trans-DDP进行了比较研究。尽管在SV 40感染的绿色猴CV-1细胞中，抑制SV 40 DNA复制所需的培养基中的反式DDP是顺式DDP的14倍，但当等摩尔量与SV 40 DNA在体内结合时，这两种异构体在抑制复制方面同样有效。由于两种异构体以相似的速率转运到CV-1细胞中，因此差异摄取不能解释顺式DDP抑制SV 40 DNA复制的能力更强。相反，这一结果是解释的发现，顺式DDP-DNA加合物的积累不断在孵育期间，而反式DDP结合DNA达到最大值在6小时，此后显着下降。我们认为cis-DDP和trans-DDP在CV-1细胞DNA上的不同蓄积行为是由于它们在细胞内的差异修复。多种非组蛋白蛋白（包括SV 40衣壳蛋白，但几乎没有组蛋白）在体内通过顺式或反式DDP与SV 40 DNA交联。在等量的DNA结合铂下，反式DDP比顺式DDP形成更多的DNA-蛋白质交联。由于顺式-DDP类似物二氯（乙二胺）铂（II）与顺式-和反式-DDP一样有效地抑制SV 40 DNA复制，但不形成DNA-蛋白质交联，因此铂介导的DNA-蛋白质交联并不直接导致DNA复制的抑制。我们讨论了这些发现与已知的顺式顺铂的细胞毒性和抗肿瘤特性。
The mechanism of action of the antitumor drug cis-diamminedichloroplatinum(II), cis-DDP, was investigated by using the .apprx. 5200 base pair (bp) chromosome of simian virus 40 (SV40) as an in vivo chromatin model. Comparative studies were also carried out with the clinically ineffective isomer trans-DDP. Although 14 times more trans- than cis-DDP in the culture medium is required to inhibit SV40 DNA replication in SV40-infected green monkey CV-1 cells, the two isomers are equally effective at inhibiting replication when equimolar amounts are bound to SV40 DNA in vivo. Since both isomers are transported into CV-1 cells at similar rates, differential uptake cannot account for the greater ability of cis-DDP to inhibit SV40 DNA replication. Rather, this result is explained by the finding that cis-DDP-DNA adducts accumulate continuously over the incubation period, whereas trans-DDP binding to DNA reaches a maximum at 6 h and thereafter decreases dramatically. We suggest that the different accumulation behavior of cis-DDP and trans-DDP on DNA is due to their differential repair in CV-1 cells. A variety of non-histone proteins, including SV40 capsid proteins but virtually no histones, are cross-linked to SV40 DNA in vivo by either cis- or trans-DDP. More DNA-protein cross-links are formed by trans-DDP than by cis-DDP at equivalent amounts of DNA-bound platinum. Since the cis-DDP analogue dichloro(ethylenediamine)platinum(II) inhibits SV40 DNA replication as efficiently as cis- and trans-DDP but does not form DNA-protein cross-links, platinum-mediated DNA-protein cross-linking is not directly responsible for the inhibition of DNA replication. We discuss these findings in relation to the known cytotoxic and antitumor properties of cis-DDP.