Journal article
Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination
Journal of drug metabolism & toxicology, Vol.2(107), 1000107
02/02/2011
DOI: 10.4172/2157-7609.1000107
PMCID: PMC3144579
PMID: 21804948
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 ABCC-transport 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.
Details
- Title: Subtitle
- Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination
- Creators
- Dan Rudin - Mayo ClinicLiang Li - Mayo ClinicNifang Niu - Mayo ClinicKrishna R. Kalari - Mayo ClinicJudith A. Gilbert - Mayo ClinicMatthew M. Ames - Mayo ClinicLiewei Wang - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Journal of drug metabolism & toxicology, Vol.2(107), 1000107
- DOI
- 10.4172/2157-7609.1000107
- PMID
- 21804948
- PMCID
- PMC3144579
- NLM abbreviation
- J Drug Metab Toxicol
- ISSN
- 2157-7609
- eISSN
- 2157-7609
- Number of pages
- 10
- Grant note
- K22 CA130828-02 || CA / National Cancer Institute : NCI U19 GM061388-11 || GM / National Institute of General Medical Sciences : NIGMS P50 CA102701-08 || CA / National Cancer Institute : NCI R01 CA138461-03 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 02/02/2011
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701839902771
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