Organic cation transporter 2 and cisplatin nephrotoxicity

描述（由申请人提供）：顺铂是用于治疗成人和儿童多种恶性实体瘤的最广泛使用的抗癌药物之一。顺铂的临床使用与剂量限制性肾损伤（肾毒性）有关，这种损伤依赖于 p53，尽管采取了强化预防措施，但仍有三分之一的患者会出现这种情况，这种并发症可能会限制进一步的治疗，甚至威胁生命。目前尚无已知的针对顺铂引起的肾功能障碍的具体治疗方法，并且对顺铂的肾脏处理机制细节的研究仍然很少。我们最近发现顺铂的尿排泄和药物引起的肾脏损伤依赖于有机阳离子转运蛋白介导的肾小管转运。在小鼠中，发现这一过程受到两个密切相关的有机阳离子转运蛋白 Oct1 和 Oct2 的调节，这两个转运蛋白在功能上是冗余的，并且共同发挥的作用相当于人类中单一有机阳离子转运蛋白 OCT2 的作用。这些转运蛋白在肾小管细胞的基底外侧膜上高度表达，但我们发现 OCT2 在人类癌细胞系和人类实体瘤中基本上不存在，特别是在那些需要顺铂治疗的肿瘤中，例如肺癌和卵巢癌。这些发现表明 OCT2 不太可能在顺铂转运到体内肿瘤细胞中发挥作用。在当前的提案中，我们概述了三组相关研究，这些研究将进一步测试和完善我们中心假设的有效性，即靶向抑制 OCT2 功能将特异性影响顺铂在近端肾小管细胞中的积累及其下游毒性作用。 (1)使用各种小鼠模型和成年癌症患者队列，我们​​将进一步确定OCT2抑制剂对顺铂的处置和毒性的定量影响。 (2) 将进行类似的研究，以确定 p53 信号通路对同时接受 OCT2/p53 双重抑制剂的小鼠顺铂肾毒性的额外贡献。 (3) 对具有不同 OCT2 表达水平的人类肿瘤异种移植物的 nu/nu 小鼠进行的其他研究将确定该转运蛋白对顺铂相关抗癌功效的直接贡献。通过抑制调节药物进入肾近端肾小管细胞的关键肾转运蛋白来减少顺铂诱导的肾毒性，将为未来旨在改善常规临床实践中这种使人衰弱的副作用的其他研究奠定基础。

DESCRIPTION (provided by applicant): Cisplatin is one of the most widely used anticancer agents for the treatment of multiple malignant solid tumors in both adults and children. The clinical use of cisplatin is associated with dose-limiting kidney damage (nephrotoxicity), which is dependent on p53 and occurs in one-third of patients despite intensive prophylactic measures, and this complication may limit further treatment or even threaten life. There is currently no known specific treatment for cisplatin-induced renal dysfunction, and mechanistic details of renal handling of cisplatin have remained poorly studied. We have recently found that the urinary excretion of cisplatin and drug-induced damage to kidneys is dependent on organic cation transporter-mediated renal tubular transport. In mice, this process was found to be regulated by the two closely related organic cation transporters, Oct1 and Oct2, that are functionally redundant and that together fulfill a role equivalent to that of a single organic cation transporter, OCT2, in humans. These transporters are highly expressed on the basolateral membrane of renal tubular cells but we found that OCT2 is essentially absent in human cancer cell lines and human solid tumors, in particular in those for which treatment with cisplatin is indicated, such as lung cancer and ovarian cancer. These findings suggest that OCT2 is unlikely to play a role in the transport of cisplatin into tumor cells in vivo. In the current proposal, we outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT2 function will specifically affect cisplatin accumulation in proximal tubular cells and its downstream toxic effects. (1) Using various mouse models and a cohort of adult cancer patients, we will further determine the quantitative effects of OCT2 inhibitors on the disposition and toxicity of cisplatin. (2) Similar studies will be performed to determine the additional contribution of the p53 signaling pathway to cisplatin nephrotoxicity in mice concurrently receiving a dual OCT2/p53 inhibitor. (3) Additional studies in nu/nu mice bearing human tumor xenografts with variable expression levels of OCT2 will determine the direct contribution of this transporter to cisplatin-related anticancer efficacy. The demonstration of reduced cisplatin-induced nephrotoxicity through inhibition of a critical renal transporter regulating access of the drug to renal proximal tubular cells will provide the foundation for additional studies in the future aimed at ameliorating this debilitating side effect in routine clinical practice.