Hardie Megan E, Kava Hieronimus W, Murray Vincent
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Curr Pharm Des. 2016;22(44):6645-6664. doi: 10.2174/1381612822666160831101529.
Cisplatin is widely used as a cancer chemotherapeutic agent and this review covers the mechanism of action of cisplatin, cellular resistance to cisplatin, the genomic location of cisplatin adducts and the properties of DNA-targeted Pt complexes. A particular focus of this review is the interaction of Pt compounds with DNA. The technology involved in determining Pt-drug/DNA interactions has advanced and permits clearer views of this process. In particular, molecular biological techniques permit a more accurate and precise determination of the sequence specific preference of Pt adduct formation. Prospects for the sequence specific genome-wide determination of Pt adduct formation using next-generation sequencing are also discussed. Cisplatin analogues that are targeted to DNA via an attached DNA-affinic moiety are potentially beneficial anti-tumour agents. In particular the 9-aminoacridine Pt complexes possess a number of important characteristics, including activity against cisplatin-resistant cells. Their ability to circumvent resistance due to increased DNA repair may allow these DNA-targeted analogues to avoid many of the drawbacks associated with current clinical oncology treatment. This ability is thought to be due to their altered DNA sequence specificity, compared with cisplatin, where Pt adduct formation for the 9- aminoacridine Pt complexes was shifted away from consecutive guanines towards 5'-CG and 5'-GA dinucleotide sequences. Evidence for this evasion of repair processes and avoidance of cellular cisplatin resistance was found for 9-aminoacridine Pt complexes in studies with cisplatin resistant cells. The prospects for clinical use of these DNA-targeted anti-tumour agents were evaluated.
顺铂作为一种癌症化疗药物被广泛应用，本综述涵盖了顺铂的作用机制、细胞对顺铂的耐药性、顺铂加合物的基因组定位以及靶向DNA的铂配合物的性质。本综述的一个特别重点是铂化合物与DNA的相互作用。用于确定铂药物/DNA相互作用的技术已经取得进展，使得对这一过程有更清晰的认识。特别是，分子生物学技术能够更准确、精确地确定铂加合物形成的序列特异性偏好。还讨论了使用下一代测序在全基因组范围内确定铂加合物形成的序列特异性的前景。通过连接的DNA亲和部分靶向DNA的顺铂类似物是潜在有益的抗肿瘤药物。特别是9-氨基吖啶铂配合物具有许多重要特性，包括对顺铂耐药细胞的活性。它们规避因DNA修复增加而产生的耐药性的能力，可能使这些靶向DNA的类似物避免许多与当前临床肿瘤治疗相关的缺点。这种能力被认为是由于它们与顺铂相比改变了DNA序列特异性，9-氨基吖啶铂配合物的铂加合物形成从连续的鸟嘌呤转移到5'-CG和5'-GA二核苷酸序列。在对顺铂耐药细胞的研究中发现了9-氨基吖啶铂配合物逃避修复过程和避免细胞顺铂耐药性的证据。评估了这些靶向DNA的抗肿瘤药物的临床应用前景。
