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dc.contributor.authorBjånes, Tormod Karlsen
dc.contributor.authorJordheim, Lars Petter
dc.contributor.authorSchjøtt, Jan
dc.contributor.authorKamceva, Tina
dc.contributor.authorCros-Perrial, Emeline
dc.contributor.authorLanger, Anika
dc.contributor.authorde Garibay, Gorka Ruiz
dc.contributor.authorKotopoulis, Spiros
dc.contributor.authorMcCormack, Emmet
dc.contributor.authorRiedel, Bettina
dc.description.abstractCytidine deaminase (CDA) is a determinant of in vivo gemcitabine elimination kinetics and cellular toxicity. The impact of CDA activity in pancreatic ductal adenocarcinoma (PDAC) cell lines has not been elucidated. We hypothesized that CDA regulates gemcitabine flux through its inactivation and activation pathways in PDAC cell lines. Three PDAC cell lines (BxPC-3, MIA PaCa-2, and PANC-1) were incubated with 10 or 100 µM gemcitabine for 60 minutes or 24 hours, with or without tetrahydrouridine, a CDA inhibitor. Extracellular inactive gemcitabine metabolite (dFdU) and intracellular active metabolite (dFdCTP) were quantified with liquid chromatography tandem mass spectrometry. Cellular expression of CDA was assessed with real-time PCR and Western blot. Gemcitabine conversion to dFdU was extensive in BxPC-3 and low in MIA PaCa-2 and PANC-1, in accordance with their respective CDA expression levels. CDA inhibition was associated with low or undetectable dFdU in all three cell lines. After 24 hours gemcitabine incubation, dFdCTP was highest in MIA PaCa-2 and lowest in BxPC-3. CDA inhibition resulted in a profound dFdCTP increase in BxPC-3 but not in MIA PaCa-2 or PANC-1. dFdCTP concentrations were not higher after exposure to 100 versus 10 µM gemcitabine when CDA activities were low (MIA PaCa-2 and PANC-1) or inhibited (BxPC-3). The results suggest a regulatory role of CDA for gemcitabine activation in PDAC cells but within limits related to the capacity in the activation pathway in the cell lines. SIGNIFICANCE STATEMENT The importance of cytidine deaminase (CDA) for cellular gemcitabine toxicity, linking a lower activity to higher toxicity, is well described. An underlying assumption is that CDA, by inactivating gemcitabine, limits the amount available for the intracellular activation pathway. Our study is the first to illustrate this regulatory role of CDA in pancreatic ductal adenocarcinoma cell lines by quantifying intracellular and extracellular gemcitabine metabolite concentrations.en_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics (ASPET)en_US
dc.rightsNavngivelse-Ikkekommersiell 4.0 Internasjonal*
dc.titleIntracellular Cytidine Deaminase Regulates Gemcitabine Metabolism in Pancreatic Cancer Cell Linesen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.rights.holderCopyright 2020 by The Author(s)en_US
dc.source.journalDrug Metabolism And Dispositionen_US
dc.identifier.citationDrug Metabolism And Disposition. 2020, 48 (3), 153-158.en_US

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Navngivelse-Ikkekommersiell 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse-Ikkekommersiell 4.0 Internasjonal