Solute Carriers and Oxaliplatin Neurotoxicity

 描述（由申请方提供）：奥沙利铂是最广泛使用的抗癌药物之一，特别用于治疗晚期结直肠癌。奥沙利铂的临床使用与周围神经的剂量限制性损伤（神经毒性）相关，尽管采取了强化预防措施，但仍有高达90%的患者发生这种损伤，这种并发症可能限制进一步治疗，甚至威胁生命。目前尚无已知的奥沙利铂诱导的周围神经毒性的特异性治疗方法，并且对该副作用的机制细节研究不足。我们最近发现奥沙利铂的尿排泄和药物诱导的背根神经节细胞损伤依赖于有机阳离子转运蛋白介导的转运。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。这些转运体在肾小管和背根神经节细胞的基底外侧膜上高度表达，并且它们的功能可以通过非竞争性机制被各种酪氨酸激酶抑制剂调节。此外，我们发现OCT 2在人结直肠癌细胞系和人结直肠肿瘤中基本上不存在，这表明OCT 2不太可能在体内奥沙利铂转运到肿瘤细胞中发挥作用。在目前的建议中，我们概述了三组相关的研究，这些研究将进一步测试和完善我们的中心理论的有效性。 假设OCT 2功能的靶向抑制将特异性影响奥沙利铂在背根神经节中的蓄积及其下游毒性作用。(1)使用各种体外和体内模型，我们将进一步确定酪氨酸激酶抑制剂（包括达沙替尼）对OCT 2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急性和慢性奥沙利铂诱导的神经毒性的体内调节剂的作用。(3)在携带不同OCT 2表达水平的人结直肠肿瘤异种移植物的nu/nu小鼠中进行的其他研究将确定该转运蛋白对奥沙利铂相关抗癌疗效的直接贡献以及并发OCT 2抑制剂的作用。通过抑制调节药物进入背根神经节关键转运蛋白来降低奥沙利铂诱导神经毒性的证明将为未来旨在改善常规治疗中这种使人衰弱副作用的其他研究提供基础 临床实践

 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.