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Organic cation transporter 2 and cisplatin nephrotoxicity

有机阳离子转运蛋白2和顺铂肾毒性

基本信息

批准号：
8657878
负责人：
Alexander Sparreboom
金额：
$ 38.68万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-12 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657878
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

项目摘要

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.

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）相关，这取决于p53，尽管采取了强化预防措施，仍有三分之一的患者发生，这种并发症可能限制进一步治疗，甚至威胁生命。目前还没有已知的顺铂诱导的肾功能不全的特异性治疗方法，顺铂的肾脏处理机制的细节仍然研究不足。我们最近发现顺铂的尿排泄和药物引起的肾脏损害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种密切相关的有机阳离子转运蛋白Oct 1和Oct 2的调节，这两种转运蛋白在功能上是冗余的，共同发挥的作用相当于人类中单一有机阳离子转运蛋白OCT 2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OCT 2在人癌细胞系和人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，如肺癌和卵巢癌。这些发现表明，OCT 2不太可能在体内顺铂转运到肿瘤细胞中发挥作用。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OCT 2功能的靶向抑制将特异性影响顺铂在近端肾小管细胞中的蓄积及其下游毒性作用。(1)使用各种小鼠模型和一组成年癌症患者，我们将进一步确定OCT 2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信号传导途径对同时接受双重OCT 2/p53抑制剂的小鼠中顺铂肾毒性的额外贡献。(3)在携带不同OCT 2表达水平的人肿瘤异种移植物的nu/nu小鼠中进行的其他研究将确定该转运蛋白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肾小管细胞的关键肾转运蛋白，证明顺铂诱导的肾毒性降低，这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提供基础。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics.

DOI：
10.1158/1535-7163.mct-12-0926
发表时间：
2013-08
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Lancaster CS;Sprowl JA;Walker AL;Hu S;Gibson AA;Sparreboom A
通讯作者：
Sparreboom A

CCR 20th anniversary commentary: BMS-247550—microtubule stabilization as successful targeted therapy.

DOI：
10.1158/1078-0432.ccr-14-2551
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Pabla N;Sparreboom A
通讯作者：
Sparreboom A

Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy.