Stojanovska Vanesa, McQuade Rachel, Rybalka Emma, Nurgali Kulmira
College of Health and Biomedicine, Victoria University, Melbourne, Victoria. Australia.
College of Health and Biomedicine, VCollege of Health and Biomedicine, Victoria University, Melbourne, Victoriaictoria University, Melbourne. Australia.
Curr Med Chem. 2017;24(15):1520-1536. doi: 10.2174/0929867324666170112095428.
Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin, are an important class of drugs used in clinical setting to treat a variety of cancers. The cytotoxic efficacy of these drugs is mediated by the formation of inter-strand and intrastrand crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons. Although all platinum-based agents form similar DNA adducts, they are quite different in terms of activation, systemic toxicity and tolerance. Platinum-based agents are well known for their neurotoxicity and gastrointestinal side-effects which are major causes for dose limitation and treatment discontinuation compromising the efficacy of anti-cancer treatment. Accumulating evidence in non-neuronal cells shows that the copper transport system is associated with platinum drug sensitivity and resistance. There is minimal research concerning the role of copper transporters within the central and peripheral nervous systems. It is unclear whether neurons are more sensitive to platinum-based drugs, are insufficient in drug clearance, or whether platinum accumulation affects intracellular copper status and coppermediated functions. Understanding these mechanisms is important as neurotoxicity is the predominant side-effect of platinum-based chemotherapy. This review highlights the role of copper transpor ters in drug influx, differences in drug activation and side-effects caused by platinum-based agents, as well as their association with central and peripheral neuropathies and gastrointestinal toxicities.
铂类抗癌药物，包括顺铂、卡铂和奥沙利铂，是临床用于治疗多种癌症的一类重要药物。这些药物的细胞毒性作用是通过形成链间和链内交联，或在核DNA上形成铂加合物来介导的。也有证据表明，线粒体DNA在背根神经节神经元中易受铂加合物损伤。尽管所有铂类药物都会形成相似的DNA加合物，但它们在激活、全身毒性和耐受性方面却有很大差异。铂类药物以其神经毒性和胃肠道副作用而闻名，这些副作用是剂量限制和治疗中断的主要原因，会影响抗癌治疗的疗效。在非神经元细胞中积累的证据表明，铜转运系统与铂类药物的敏感性和耐药性有关。关于铜转运蛋白在中枢和外周神经系统中的作用的研究极少。尚不清楚神经元对铂类药物是否更敏感、药物清除是否不足，或者铂的积累是否会影响细胞内铜的状态和铜介导的功能。了解这些机制很重要，因为神经毒性是铂类化疗的主要副作用。本综述重点介绍了铜转运蛋白在药物流入中的作用、铂类药物引起的药物激活差异和副作用，以及它们与中枢和外周神经病变及胃肠道毒性的关系。
