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.

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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Timmer, William C
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St. Jude Children's Research Hospital
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Sprowl, Jason A; Lancaster, Cynthia S; Pabla, Navjotsingh et al. (2014) Cisplatin-induced renal injury is independently mediated by OCT2 and p53. Clin Cancer Res 20:4026-35
Sparreboom, Alex; Mathijssen, Ron H J (2014) Hepatic uptake transporters and docetaxel disposition in mice-letter. Clin Cancer Res 20:4167
Sprowl, Jason A; Sparreboom, Alex (2014) Uptake carriers and oncology drug safety. Drug Metab Dispos 42:611-22
Sprowl, Jason A; Ciarimboli, Giuliano; Lancaster, Cynthia S et al. (2013) Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A 110:11199-204
Sprowl, Jason A; Mathijssen, Ron H; Sparreboom, Alex (2013) Can erlotinib ameliorate cisplatin-induced toxicities? J Clin Oncol 31:3442-3
Sprowl, Jason A; Ness, Rachel A; Sparreboom, Alex (2013) Polymorphic transporters and platinum pharmacodynamics. Drug Metab Pharmacokinet 28:19-27
Zimmerman, Eric I; Hu, Shuiying; Roberts, Justin L et al. (2013) Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res 19:1458-66
Lancaster, Cynthia S; Sprowl, Jason A; Walker, Aisha L et al. (2013) Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics. Mol Cancer Ther 12:1537-44
Sprowl, J A; van Doorn, L; Hu, S et al. (2013) Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance. Clin Pharmacol Ther 94:585-92
de Graan, Anne-Joy M; Elens, Laure; Sprowl, Jason A et al. (2013) CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 19:3316-24

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