Woźniak Katarzyna, Błasiak Janusz
Department of Molecular Genetics, University of Łódź, S. Banacha 12/16, 90-237 Łódź, Poland.
Acta Biochim Pol. 2002;49(3):583-96.
Anticancer activity of cisplatin (cis-diamminedichloroplatinum) is believed to result from its interaction with DNA. The drug reacts with nucleophilic sites in DNA forming monoadducts as well as intra- and interstrand crosslinks. DNA-cisplatin adducts are specifically recognized by several proteins. They can be divided into two classes. One constitutes proteins which recognize DNA damage as an initial step of the nucleotide excision and mismatch repair pathways. The other class contains proteins stabilizing cellular DNA-protein and protein-protein complexes, including non-histone proteins from the HMG (high-mobility-group) family. They specifically recognize 1,2-interstrand d(GpG) and d(ApG) crosslinks of DNA-cisplatin adducts and inhibit their repair. Many HMG-domain proteins can function as transcription factors, e.g. UBF, an RNA polymerase I transcription factor, the mammalian testis-determining factor SRY and the human mitochondrial transcription factor mtTFA. Moreover, it seems that some proteins, which probably recognize DNA-cisplatin adducts non-specifically, e.g. actin and other nuclear matrix proteins, can disturb the structural and functional organization of the nucleus and whole cell. The formation of complexes between DNA and proteins in the presence of cisplatin and the changes in the cell architecture may account for the drug cytotoxicity.
顺铂（顺二氨二氯铂）的抗癌活性被认为源于其与DNA的相互作用。该药物与DNA中的亲核位点反应，形成单加合物以及链内和链间交联。DNA-顺铂加合物被几种蛋白质特异性识别。它们可分为两类。一类是将DNA损伤识别为核苷酸切除和错配修复途径起始步骤的蛋白质。另一类包含稳定细胞DNA-蛋白质和蛋白质-蛋白质复合物的蛋白质，包括来自HMG（高迁移率族）家族的非组蛋白。它们特异性识别DNA-顺铂加合物的1,2-链间d(GpG)和d(ApG)交联并抑制其修复。许多HMG结构域蛋白可作为转录因子发挥作用，例如RNA聚合酶I转录因子UBF、哺乳动物睾丸决定因子SRY和人类线粒体转录因子mtTFA。此外，似乎一些可能非特异性识别DNA-顺铂加合物的蛋白质，例如肌动蛋白和其他核基质蛋白，会干扰细胞核和整个细胞的结构和功能组织。在顺铂存在的情况下DNA与蛋白质之间复合物的形成以及细胞结构的变化可能是该药物细胞毒性的原因。
