Organic cation transporter 2 and cisplatin nephrotoxicity

描述（由申请人提供）：顺铂是治疗成人和儿童多发性恶性实体瘤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害（肾毒性）相关，这依赖于p53，尽管采取了强化预防措施，但仍有三分之一的患者发生这种并发症，这种并发症可能限制进一步治疗甚至威胁生命。目前还没有已知的针对顺铂引起的肾功能障碍的特异性治疗方法，并且对顺铂肾脏处理的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体介导的肾小管转运。在小鼠中，这一过程被发现是由两个密切相关的有机阳离子转运蛋白Oct1和Oct2调控的，这两个有机阳离子转运蛋白在功能上是冗余的，它们共同发挥的作用相当于一个有机阳离子转运蛋白Oct2在人类中的作用。这些转运蛋白在肾小管细胞的基底外膜上高度表达，但我们发现OCT2在人类癌细胞系和人类实体肿瘤中基本缺失，特别是在那些需要顺铂治疗的肿瘤中，如肺癌和卵巢癌。这些发现提示OCT2不太可能在体内顺铂转运到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的中心假设的有效性，即靶向抑制OCT2功能将特异性地影响顺铂在近端小管细胞中的积累及其下游毒性作用。(1)通过多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双抑制剂的小鼠顺铂肾毒性的额外贡献。(3)对携带不同OCT2表达水平的人类肿瘤异种移植物的nu/nu小鼠的进一步研究将确定该转运体对顺铂相关抗癌疗效的直接贡献。通过抑制调节药物进入肾近端小管细胞的关键肾转运蛋白，顺铂诱导的肾毒性降低的证明将为未来旨在改善常规临床实践中这种衰弱副作用的进一步研究提供基础。

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. PUBLIC HEALTH RELEVANCE: Cisplatin is among the most effective and widely prescribed anticancer agents but its clinical use is associated with dose-limiting, irreversible kidney damage (nephrotoxicity). Using a unique genetic mouse model, we found that cisplatin nephrotoxicity is dependent on transporter-mediated drug uptake into renal tubular cells. Our proposed studies are of direct human relevance because targeted interference with the identified renal transport system may mitigate the incidence and severity of this debilitating side effect in humans.