Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity

K K Filipski, R H Mathijssen, T S Mikkelsen, A H Schinkel, A Sparreboom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

330 Citations (Scopus)

Abstract

Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from severe cisplatin-induced renal tubular damage. Subsequently, we found that a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene SLC22A2 (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients. Collectively, these results indicate the critical importance of OCT2 in the renal handling and related renal toxicity of cisplatin and provide a rationale for the development of new targeted approaches to mitigate this debilitating side effect.

Original languageEnglish
Pages (from-to)396-402
Number of pages7
JournalClinical Pharmacology & Therapeutics
Volume86
Issue number4
DOIs
Publication statusPublished - Oct 2009

Research programs

  • EMC MM-03-86-08

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