Abstract 885: Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine cytotoxic action.

Abstract

Bendamustine hydrochloride is a cytotoxic agent that encompasses structural features of alkylating and nucleoside-derived drugs. This drug is currently used in the treatment of several haemotological malignancies; among them Chronic Lymphocytic Leukemia (CLL). CLL is the most common leukemia in Western countries and is characterized by the accumulation of monoclonal CD5+ B cells in the blood, bone marrow, lymph nodes, spleen and other organs. The pathways facilitating the uptake of bendamustine hydrochloride into target cells still remain poorly understood. Here we have addressed this issue by monitoring the interaction of the drug with selected plasma membrane transporter candidates, which might be relevant to bendamustine pharmacokinetics and pharmacodynamics. We have used a panel of HEK293 cells stably expressing selected drug transporter proteins to prove that bendamustine is able to interact with human Organic Cation Transporter 1 (hOCT1) with a Ki of 140+/-10 μM, as deduced from cis-inhibition studies using tritiated 1-methyl-4-phenylpyridinium (MPP+) as hOCT model substrate. Genetic variants known to modify substrate/transporter interactions, some of them with high allelic frequency in humans, were also tested and, in particular, hOCT1M420Del showed a significant decrease in its affinity for the drug (Ki value 234+/-24 μM, p<0.05 vs the wild type transporter). The whole panel of hOCT1 and hOCT1 allelic variants were also tested for bendamustine-induced cytotoxicity and data consistent with bendamustine being a hOCT1 substrate were obtained. This was based upon the finding that hOCT1 expression triggered increased sensitivity to the drug and variants known to decrease drug-transporter affinity interactions were also shown to induce resistance. hOCT1 is expressed in CLL cells and genotyping of a cohort of 125 CLL patients is now allowing the analysis of the relationships between particular genetic variants and ex vivo bendamustine-induced cytotoxicity, thus opening the possibility that hOCT1 genotyping might be a useful tool in optimizing bendamustine-based therapies. Citation Format: Cristina Arimany-Nardi, Arnau Montraveta, Eriong Lee-Vergés, Hermann Koepsell, Dolors Colomer, Marçal Pastor-Anglada. Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine cytotoxic action. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 885. doi:10.1158/1538-7445.AM2013-885