Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2.

Jason A Sprowl, Giuliano Ciarimboli, Cynthia S Lancaster, Hugh Giovinazzo, Alice A Gibson, Guoqing Du, Laura J Janke, Guido Cavaletti, Anthony F Shields, Alex Sparreboom

Proceedings of the National Academy of Sciences of the United States of America 2013 Jul 02

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Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.

Citation

Jason A Sprowl, Giuliano Ciarimboli, Cynthia S Lancaster, Hugh Giovinazzo, Alice A Gibson, Guoqing Du, Laura J Janke, Guido Cavaletti, Anthony F Shields, Alex Sparreboom. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proceedings of the National Academy of Sciences of the United States of America. 2013 Jul 02;110(27):11199-204