Solute Carriers and Oxaliplatin Neurotoxicity

溶质载体和奥沙利铂神经毒性

• 批准号: 8882604
• 负责人: Alexander Sparreboom
• 金额: $ 14.86万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882604
• 关键词: Acute; Adult; Adverse effects; Affect; Animal Model; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Carcinoma; Cells; Chemicals; Child; Chronic; Clinical; Colorectal Cancer; Colorectal Neoplasms; Complication; Dasatinib; Development; Dose-Limiting; Drug Kinetics; Evaluation; Event; Excretory function; Foundations; Future; Genetic; Goals; Human; Hybrids; In Situ; In Vitro; Incidence; Kidney; Large Intestine Carcinoma; Lead; Libraries; Life; Malignant Epithelial Cell; Mammalian Cell; Measures; Mediating; Mus; Neuroglia; Organic Cation Transporter; POU2F1 gene; POU2F2 gene; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Phosphotransferases; Physiological; Play; Process; Prospective Studies; Proteomics; RNA Interference; Role; Severities; Source; Specificity; Spinal Ganglia; System; Testing; Toxic effect; Treatment Protocols; Tubular formation; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Work; base; basolateral membrane; chemotherapy; clinical practice; colon cancer cell line; ganglion cell; in vivo; in vivo Model; inhibitor/antagonist; insight; mouse model; neoplastic cell; neurotoxic; neurotoxicity; oxaliplatin; prevent; prophylactic; public health relevance; response; satellite cell; screening; solute; treatment strategy; tumor growth; tumor xenograft; uptake; urinary

 DESCRIPTION (provided by applicant): Oxaliplatin is one of the most widely used anticancer agents, specifically for the treatment of advanced colorectal cancer carcinomas. The clinical use of oxaliplatin is associated with dose-limiting damage to peripheral nerves (neurotoxicity), which occurs in up to 90% 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 oxaliplatin-induced peripheral neurotoxicity, and mechanistic details of this side effect have remained poorly studied. We have recently found that the urinary excretion of oxaliplatin and drug- induced damage to dorsal root ganglia cells is dependent on organic cation transporter-mediated 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 and dorsal root ganglia cells, and their function can be modulated by various tyrosine kinase inhibitors through a non-competitive mechanism. Moreover, we found that OCT2 is essentially absent in human colorectal cancer cell lines and human colorectal tumors, suggesting that OCT2 is unlikely to play a role in the transport of oxaliplatin 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 oxaliplatin accumulation in dorsal root ganglia and its downstream toxic effects. (1) Using various in vitro and in vivo models, we will further determine the qualitative and quantitative effects of tyrosine kinase inhibitors, including dasatinib, on the function of OCT2. (2) Studies will be performed to determine the effect of tyrosine kinase inhibitors as in vivo modulators of acute and chronic oxaliplatin-induced neurotoxicity. (3) Additional studies in nu/nu mice bearing human colorectal tumor xenografts with variable expression levels of OCT2 will determine the direct contribution of this transporter to oxaliplatin-related anticancer efficacy, and the effects of concurrent OCT2 inhibitors. The demonstration of reduced oxaliplatin-induced neurotoxicity through inhibition of a critical transporter regulating access of the drug to dorsal root ganglia will provide the foundatin for additional studies in the future aimed at ameliorating this debilitating side effect in routine clinical practice.

 描述(申请人提供)：奥沙利铂是应用最广泛的抗癌药物之一，专门用于治疗晚期结直肠癌。奥沙利铂的临床应用与周围神经的剂量限制性损害(神经毒性)有关，尽管采取了密集的预防措施，高达90%的患者仍会发生这种情况，这种并发症可能会限制进一步的治疗，甚至威胁到生命。目前尚无已知的针对奥沙利铂所致周围神经毒性的特效药，这种副作用的机制细节仍未得到很好的研究。我们最近发现，奥沙利铂的尿排出和药物对背根神经节细胞的损伤依赖于有机阳离子转运体介导的转运。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和背根神经节细胞的基底膜上高度表达，其功能可被各种酪氨酸激酶抑制剂通过非竞争性机制调节。此外，我们发现OCT2在人结直肠癌细胞系和人结直肠肿瘤中基本上是缺失的，这表明OCT2在体内不太可能在奥沙利铂进入肿瘤细胞的转运中发挥作用。在目前的建议中，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央 假设靶向抑制OCT2功能将特异性地影响奥沙利铂在背根节的积聚及其下游的毒性效应。(1)利用不同的体外和体内模型，进一步确定酪氨酸激酶抑制剂，包括达沙替尼，对OCT2功能的定性和定量影响。(2)将进行研究，以确定酪氨酸激酶抑制剂作为体内调节剂对奥沙利铂所致的急性和慢性神经毒性的影响。(3)对携带不同表达水平的OCT2的nu/nu小鼠的进一步研究将确定该转运体对奥沙利铂相关抗癌疗效的直接贡献，以及同时使用OCT2抑制剂的效果。通过抑制调节药物进入背根神经节的关键转运蛋白来减少奥沙利铂引起的神经毒性，将为未来旨在改善常规治疗中这种衰弱副作用的进一步研究提供基础。 临床实践。