Organic cation transporter 2 and cisplatin nephrotoxicity

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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.