Organic cation transporter 2 and cisplatin nephrotoxicity

有机阳离子转运蛋白2和顺铂肾毒性

• 批准号: 8260216
• 负责人: Alexander Sparreboom
• 金额: $ 39.86万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260216
• 关键词: Adult; Adverse effects; Affect; Animal Model; Antineoplastic Agents; Biochemical; Cancer Patient; Cancer cell line; Cations; Cells; Chemicals; Child; Cimetidine; Cisplatin; Clinical; Complication; Development; Dose-Limiting; Evaluation; Excretory function; Foundations; Functional disorder; Future; Genetic; Goals; Human; Hybrids; In Vitro; Incidence; Kidney; Lead; Life; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measures; Mediating; Mus; Nephrotoxic; Organic Cation Transporter; POU2F2 gene; Patients; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Play; Process; Prospective Studies; Role; Severities; Signal Transduction; Solid Neoplasm; Source; System; Testing; Toxic effect; Treatment Protocols; Tubular formation; Work; base; basolateral membrane; chemotherapy; clinical practice; cohort; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; nephrotoxicity; p53 Signaling Pathway; pifithrin; prevent; prophylactic; public health relevance; renal tubular transport; response; treatment strategy; tumor growth; tumor xenograft; uptake; urinary

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.

描述(申请人提供)：顺铂是最广泛使用的抗癌药物之一，用于治疗成人和儿童的多发性恶性实体瘤。顺铂的临床应用与剂量限制性肾损害(肾毒性)有关，这种损害依赖于P53，尽管采取了密集的预防措施，但仍有三分之一的患者发生，这种并发症可能限制进一步的治疗，甚至威胁生命。目前尚无已知的针对顺铂所致肾功能障碍的特效治疗方法，对顺铂肾脏处理机制的细节研究也很少。我们最近发现，顺铂的尿排出和药物对肾脏的损害依赖于有机阳离子转运体介导的肾小管转运。在小鼠身上，这一过程被发现受到两个密切相关的有机阳离子转运体Oct1和Oct2的调控，这两个转运体在功能上是多余的，共同发挥的作用相当于人类中单一的有机阳离子转运体OCT2。这些转运蛋白在肾小管细胞的基底膜上高度表达，但我们发现OCT2在人类癌细胞株和人类实体瘤中基本上是缺失的，特别是在那些需要顺铂治疗的肿瘤中，如肺癌和卵巢癌。这些发现表明，OCT2不太可能在体内顺铂进入肿瘤细胞的运输中发挥作用。在目前的提案中，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功能将专门影响顺铂在近端肾小管细胞中的积累及其下游毒性效应。(1)利用不同的小鼠模型和一组成人癌症患者，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，以确定在同时接受OCT2/P53双重抑制剂的小鼠中，P53信号通路对顺铂肾毒性的额外贡献。(3)在携带OCT2不同表达水平的人肿瘤异种移植瘤的nu/nu小鼠上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脏转运体来减少顺铂引起的肾毒性，将为未来在常规临床实践中旨在改善这种衰弱副作用的进一步研究提供基础。 公共卫生相关性：顺铂是最有效和最广泛使用的抗癌药物之一，但其临床应用与剂量有限、不可逆转的肾损害(肾毒性)有关。利用一种独特的小鼠遗传模型，我们发现顺铂的肾毒性依赖于转运体介导的药物进入肾小管细胞的摄取。我们建议的研究具有直接的人类相关性，因为对已识别的肾脏运输系统进行靶向干预可能会减轻这种令人衰弱的副作用在人类中的发生率和严重性。