ArticleDrug metabolism and disposition: the biological fate of chemicals2020
Intracellular Cytidine Deaminase Regulates Gemcitabine Metabolism in Pancreatic Cancer Cell Lines.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 44 citations in OpenAlex.
- A CXCR4 targeting peptide delivered by silica nanoparticles eliminates migrating cancer stem cells in pancreatic ductal adenocarcinoma.Scientific reports · 2026Article
- Sensitising PDAC to Gemcitabine by Suppressing NF-κB Pathway and Enhancing Apoptosis.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Bioinformatics analysis identifies NT5M modulates immune evasion through PD-L1 via CXCL8 in pancreatic adenocarcinoma.Scientific reports · 2025Article
- Review
- Molecular Imaging: Unveiling Metabolic Abnormalities in Pancreatic Cancer.International journal of molecular sciences · 2025Review
- CUB domain-containing protein 1 signaling dysregulates gemcitabine metabolism contributing to therapeutic resistance in T24 cells.PloS one · 2025Article
- Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A.Beilstein journal of organic chemistry · 2024Article
- Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A.Organic & biomolecular chemistry · 2023Article
- A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance.International journal of molecular sciences · 2023Article
- Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review.Cancers · 2022Review
- Article
- Metabolic syndrome related gene signature predicts the prognosis of patients with pancreatic ductal carcinoma. A novel link between metabolic dysregulation and pancreatic ductal carcinoma.Cancer cell international · 2021Article
- Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration.Current issues in molecular biology · 2021Article
- hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA.Cancers · 2021Article
- Gemcitabine-loaded microbubble system for ultrasound imaging and therapy.Acta biomaterialia · 2021Article
- Cytidine deaminase can deaminate fused pyrimidine ribonucleosides.Organic & biomolecular chemistry · 2021Article
- mFrontiers in oncology · 2021Article
- Article
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10 authors at 1 institution in 2 countries.
Funding
Abstract
Cytidine 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.
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