Repair capacity for Platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy
Repair capacity for Platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy
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DOI：
10.1523/jneurosci.0523-07.2007
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发表时间：
2007-08-29
影响因子：
5.3
通讯作者：
Thomale, Juergen
中科院分区：
文献类型：
--
作者：
Dzagnidze, Anna;Katsarava, Zaza;Thomale, Juergen
强效抗肿瘤药物顺铂的显著神经毒性经常导致周围多发性神经病（PNP）的发作，这被认为是最初由受影响组织的核DNA中的铂化产物引发的。为了进一步阐明分子机制，我们分析了在小鼠模型中的形成和处理的主要顺铂诱导的DNA加合物（鸟嘌呤链内交联）在不同的神经元细胞类型的加合物特异性单克隆抗体。比较顺铂注射小鼠的加合物动力学，无论是熟练或缺乏核苷酸切除修复（NER）功能，揭示了这种DNA修复途径在保护神经系统的分化细胞过度形成这种病变的重要作用。因此，长期暴露于顺铂导致未修复的链内交联在NER功能障碍小鼠的神经元细胞中加速积累。这些动物的背根神经节（DRG）细胞中的加合物水平增加与其感觉神经系统的PNP样功能障碍的早期发作相一致。独立于各自的修复表型，在给定的累积剂量下，DRG神经元中持续存在的DNA交联的量与通过神经电图测量的感觉障碍的程度显著相关。总的来说，这些发现表明了一种新的模型，在原代神经元细胞中处理顺铂加合物，并强调了有效的DNA修复能力在靶细胞治疗诱导PNP的个体风险中的关键作用。
The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy ( PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct ( guanine-guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair ( NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion ( DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.