Organic Cation Transporter 2 Mediates Cisplatin-Induced Oto- and Nephrotoxicity and Is a Target for Protective Interventions
Organic Cation Transporter 2 Mediates Cisplatin-Induced Oto- and Nephrotoxicity and Is a Target for Protective Interventions
复制标题
DOI：
10.2353/ajpath.2010.090610
复制
发表时间：
2010-03-01
影响因子：
6
通讯作者：
Schlatter, Eberhard
中科院分区：
文献类型：
--
作者：
Ciarimboli, Giuliano;Deuster, Dirk;Schlatter, Eberhard
有效的化疗药物顺铂的使用受到其严重副作用的限制，如耳毒性和肾毒性。耳毒性对儿童来说是一个特别重要的问题，因为耳聋阻碍了他们的语言和心理社会发展。最近，有机阳离子转运蛋白（OCT）被确定为顺铂的细胞摄取机制。在本研究中，我们在体内模型中研究了OCT在顺铂耳毒性和肾毒性发展中的作用。在野生型和OCT 1/2双敲除（KO）小鼠中研究了顺铂治疗对肾脏（24小时葡萄糖、水和蛋白质排泄）和听力（听性脑干反应）的功能影响。顺铂治疗敲除小鼠后，未观察到耳毒性迹象，仅观察到轻度肾毒性。野生型小鼠与顺铂和有机阳离子西咪替丁联合给药可防止耳毒性和部分肾毒性。这是我们首次发现OCT 2在耳蜗毛细胞中表达。此外，来自儿科肿瘤的顺铂敏感性细胞系显示OCT的mRNA不表达，表明旨在通过在肾近端小管和耳蜗毛细胞中竞争OCT 2介导的顺铂摄取来降低顺铂毒性的治疗方法的可行性。这些发现对于建立旨在最大化顺铂的抗肿瘤作用同时降低毒性风险的化疗方案非常重要。(Am J Pathol 2010，176：1169-1180; DOI：10.2353/ajpath.2010.090610）
The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wildtype and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities. (Am J Pathol 2010,176:1169-1180; DOI: 10.2353/ajpath.2010.090610)