alexa Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination | OMICS International
ISSN: 2157-7609

Journal of Drug Metabolism & Toxicology
Open Access

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Research Article

Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination

Dan Rudin1, Liang Li1, Nifang Niu1, Krishna R. Kalari2, Judith A. Gilbert1, Matthew M. Ames1 and Liewei Wang1*

1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905

2Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905

*Corresponding Author:
Dr. Liewei Wang, MD, PhD
Division of Clinical Pharmacology
Department of Molecular Pharmacology and Experimental
Therapeutics, Mayo Clinic, 200 First Street SW
Rochester, MN 55905 USA
Tel: (507) 284-5264
Fax: (507) 284-4455
E-mail: [email protected]

Received Date: December 22, 2011; Accepted Date: January 30, 2011; Published Date: February 02, 2011

Citation: Rudin D, Li L, Niu N, Kalari KR, Gilbert JA, et al. (2011) Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination. J Drug Metab Toxicol 2:107. doi: 10.4172/2157-7609.1000107

Copyright: © Rudin D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Gemcitabine is a cytidine analogue used in the treatment of various solid tumors. Little is known about how gemcitabine and its metabolites are transported out of cells. We set out to study the efflux of gemcitabine and the possible consequences of that process in cancer cells. We observed the efflux of gemcitabine and its deaminated metabolite, 2',2'-difluorodeoxyuridine (dFdU) using high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) after gemcitabine treatment. Non-selective ABCCtransport inhibition with probenecid significantly increased intracellular dFdU concentrations, with a similar trend observed with verapamil, a non-selective ABCB1 and ABCG2 transport inhibitor. Neither probenecid nor verapamil altered intracellular gemcitabine levels after the inhibition of deamination with tetrahydrourudine, suggesting that efflux of dFdU, but not gemcitabine, was mediated by ABC transporters. MTS assays showed that probenecid increased sensitivity to gemcitabine. While dFdU displayed little cytotoxicity, intracellular dFdU accumulation inhibited cytidine deaminase, resulting in increased gemcitabine levels and enhanced cytotoxicity. Knockdown of ABCC3, ABCC5 or ABCC10 individually did not significantly increase gemcitabine sensitivity, suggesting the involvement of multiple transporters. In summary, ABCC-mediated efflux may contribute to gemcitabine resistance through increased dFdU efflux that allows for the continuation of gemcitabine deamination. Reversing efflux-mediated gemcitabine resistance may require broad-based efflux inhibition.

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