ArticleOncotarget2012
High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects.
Article in Oncotarget, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells.Cell death & disease · 2018Pooled it
- Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.Seminars in hematology · 2021Trial
- Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.PLoS medicine · 2017Trial
- An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma.Oncotarget · 2015Trial
- Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance.Nature communications · 2026Article
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- Uridine as a hub in cancer metabolism and RNA biology.Experimental & molecular medicine · 2025Review
- Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS.The EMBO journal · 2024Article
- Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy.Cell reports · 2023Article
- DCK confers sensitivity of DCTD-positive cancer cells to oxidized methylcytidines.Protein & cell · 2023Article
- Epigenetic targets in B- and T-cell lymphomas: latest developments.Therapeutic advances in hematology · 2023Review
- Targeting Genetic Modifiers of HBG Gene Expression in Sickle Cell Disease: The miRNA Option.Molecular diagnosis & therapy · 2022Review
- 5-Aza-4'-thio-2'-deoxycytidine, a New Orally Bioavailable Nontoxic "Best-in-Class": DNA Methyltransferase 1-Depleting Agent in Clinical Development.The Journal of pharmacology and experimental therapeutics · 2021Review
- Exploring epigenetic and microRNA approaches for γ-globin gene regulation.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- Targeting Epigenetic Mechanisms to Treat Alcohol Use Disorders (AUD).Current pharmaceutical design · 2021Article
- Chronic myelomonocytic leukemia diagnosis and management.Leukemia · 2021Review
- Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation atScientific reports · 2021Article
- Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.Leukemia · 2021Article
- Decitabine mildly attenuatesEJHaem · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
We document for the first time that sanctuary in an organ which expresses high levels of the enzyme cytidine deaminase (CDA) is a mechanism of cancer cell resistance to cytidine analogues. This mechanism could explain why historically, cytidine analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy in vitro. Importantly, this mechanism of resistance can be readily reversed, without increasing toxicity to sensitive organs, by combining a cytidine analogue with an inhibitor of cytidine deaminase (tetrahydrouridine). Specifically, CDA rapidly metabolizes cytidine analogues into inactive uridine counterparts. Hence, to determine if sheltering/protection of cancer cells in organs which express high levels of CDA (e.g., liver) is a mechanism of resistance, we utilized a murine xenotransplant model of myeloid cancer that is sensitive to epigenetic therapeutic effects of the cytidine analogue decitabine in vitro and hepato-tropic in vivo. Treatment of tumor-bearing mice with decitabine (subcutaneous 0.2mg/kg 2X/week) doubled median survival and significantly decreased extra-hepatic tumor burden, but hepatic tumor burden remained substantial, to which the animals eventually succumbed. Combining a clinically-relevant inhibitor of CDA (tetrahydrouridine) with a lower dose of decitabine (subcutaneous 0.1mg/kg 2X/week) markedly decreased liver tumor burden without blood count or bone marrow evidence of myelotoxicity, and with further improvement in survival. In conclusion, sanctuary in a CDA-rich organ is a mechanism by which otherwise susceptible cancer cells can resist the effects of decitabine epigenetic therapy. This protection can be reversed without increasing myelotoxicity by combining tetrahydrouridine with a lower dose of decitabine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.