Mutagenicity and genotoxicity of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum(II).
Mutagenicity and genotoxicity of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum(II).
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抗肿瘤药物顺式二氨二氯铂 (II) 主要 DNA 加合物的致突变性和遗传毒性。
DOI：
10.1021/bi00054a031
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发表时间：
1993
期刊：
影响因子：
2.9
通讯作者：
Essigmann,JM
中科院分区：
文献类型：
--
作者：
Bradley,LJ;Yarema,KJ;Lippard,SJ;Essigmann,JM
摘要：本文研究了抗肿瘤药物顺铂的主要DNA加合物顺式-[Pt (NH3) 2 {d (GpG)- iv7 (1),- 7v7 (2)}]（G* G*）在大肠杆菌中的致突变性和遗传毒性。构建了一个双噬菌体Ml3基因组，在（-）链的特定位置含有G* G*加合物。与未镀铂的对照基因组相比，单铂双基因组的存活率为22%，而在紫外线照射诱导SOS应答的细胞中，这一数值上升至38%。单铂化单链基因组也产生了。单链和双链基因组在体内的复制产生了依赖于sos的靶向突变，频率分别为1.3%和0.16%。G* G*在单链和双链DNA中的诱变特异性是惊人的，80-90%的突变发生在S'-铂化的G上，大约80%的突变发生在该位点的G - t翻转。提出了一个突变模型来解释这种突变特异性，就目前对铂- dna加合物结构的理解而言。二-二胺二氯铂（II）(di-DDP)* 1 iii是一种主要用于治疗卵巢和睾丸肿瘤的高效药物（Loehrer & Einhorn, 1984）。双ddp的生物学效应被认为是由药物与DNA的共价结合引起的（Bruhn et al., 1990）。最丰富的DNA加合物是di-[Pt (NH3) 2 {d (GpG)- a7 (l),- a7 (2)}](G* G*), di-[Pt (NH3) 2 {d (ApG)- n7 (l),- a7 (2)}]（A* G*）和di-[Pt (NH3) 2 {d (GpNpG)- 7v7 (l),- n7(3)}]链内交联，占与DNA结合的药物分子的90% (Fichtinger-Schepman等，1985;Eastman，
Revised Manuscript Received October 19, 1992 abstract: The mutagenicity and genotoxicity of cis-[Pt (NH3) 2 {d (GpG)-iV7 (1),-7V7 (2)}](G* G*), the major DNA adduct of the antitumor drug cisplatin, has been investigated in Escherichia coli. A duplex bacteriophage Ml3 genome was constructed to contain the G* G* adduct at a specific site in the (-) strand. The singly platinated duplex genome exhibited a survival of 22% relative to that of the unplatinated control genomes, and this value rose to 38% in cells treatedwith ultraviolet light to induce the SOS response. Singly platinated single-stranded genomes were also produced. Replication of the single-and double-stranded genomes in vivo yielded SOS-dependent, targeted mutations at frequencies of 1.3% and 0.16%, respectively. The mutagenic specificity of G* G* inboth single-and double-stranded DNA was striking in that 80-90% of the mutations occurred at the S'-platinated G. Approximately 80% of the mutations were G—T transversions at that site. A model of mutagenesis is presented to explain thismutational specificity with respect to current understanding of platinum-DNA adduct structure. di-Diamminedichloroplatinum (II)(di-DDP)* 1 IIis a highly effective drug used mainly in the treatment for ovarian and testicular tumors (Loehrer & Einhorn, 1984). Thebiological effects of di-DDP are believed to arise from covalent binding of the drug to DNA (Bruhn et al., 1990). The most abundant DNA adducts are thedi-[Pt (NH3) 2 {d (GpG)-A7 (l),-A7 (2)}](G* G*), di-[Pt (NH3) 2 {d (ApG)-N7 (l),-A7 (2)}](A* G*), and di-[Pt (NH3) 2 {d (GpNpG)-7V7 (l),-N7 (3)}] intrastrand cross-links, accounting collectively for> 90% of the drug molecules bound to DNA (Fichtinger-Schepman et al., 1985; Eastman,