Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Domagkstr. 3a, 48149 Münster, Germany.
Am J Pathol. 2010 Mar;176(3):1169-80. doi: 10.2353/ajpath.2010.090610. Epub 2010 Jan 28.
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 wild-type 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.
有效抗肿瘤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。耳毒性是儿童特别关注的问题，因为耳聋会阻碍他们的语言和社会心理发展。最近，有机阳离子转运体 (OCT) 在体外被鉴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。研究了野生型和 OCT1/2 双敲除 (KO) 小鼠中顺铂治疗对肾脏（24 小时葡萄糖、水和蛋白质排泄）和听力（听觉脑干反应）的功能影响。敲除小鼠用顺铂处理后，未观察到耳毒性迹象，仅观察到轻度肾毒性。野生型小鼠用顺铂和有机阳离子西咪替丁联合治疗可预防耳毒性和部分肾毒性。我们首次表明，OCT2 在耳蜗毛细胞中表达。此外，来自儿科肿瘤的顺铂敏感细胞系没有表达 OCTs 的 mRNA，这表明通过竞争 OCT2 介导的顺铂摄取来减少肾近端肾小管和耳蜗毛细胞中顺铂毒性的治疗方法是可行的。这些发现对于建立旨在最大限度地发挥顺铂抗肿瘤作用同时降低毒性风险的化疗方案非常重要。
