Summary: An inhibitor of nucleotide metabolism.

Top Publications

  1. Kreis W, Chan K, Budman D, Schulman P, Allen S, Weiselberg L, et al. Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours. Cancer Res. 1988;48:1337-42 pubmed
    When 1-beta-D-arabinofuranosylcytosine (ara-C), 25 mg/m2, is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m2 to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed ..
  2. Beumer J, Parise R, Newman E, Doroshow J, Synold T, Lenz H, et al. Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol. 2008;62:363-8 pubmed
    ..FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-..
  3. Beumer J, Eiseman J, Gilbert J, Holleran J, Yellow Duke A, Clausen D, et al. Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice. Cancer Chemother Pharmacol. 2011;67:421-30 pubmed publisher
    ..3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine ..
  4. Beumer J, Eiseman J, Parise R, Florian J, Joseph E, D Argenio D, et al. Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice. Cancer Chemother Pharmacol. 2008;62:457-64 pubmed
    ..3,4,5,6-tetrahydrouridine (THU) is a potent CD inhibitor that has been applied preclinically and clinically as a modulator of cytidine ..
  5. Beumer J, Eiseman J, Parise R, Joseph E, Covey J, Egorin M. Modulation of gemcitabine (2',2'-difluoro-2'-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 3,4,5,6-tetrahydrouridine. Clin Cancer Res. 2008;14:3529-35 pubmed publisher
    ..v., with associated costs and limitations in administration schedules. 3,4,5,6-Tetrahydrouridine (THU) is a potent CD inhibitor with a 20% oral bioavailability...
  6. Alcazar O, Achberger S, Aldrich W, Hu Z, Negrotto S, Saunthararajah Y, et al. Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J Cancer. 2012;131:18-29 pubmed publisher
    ..limit high peak drug levels that cause cytotoxicity and increase exposure time for DNMT1 depletion, and with tetrahydrouridine to decrease decitabine metabolism and further increase exposure time, inhibited tumor growth and increased ..
  7. Eliopoulos N, Cournoyer D, Momparler R. Drug resistance to 5-aza-2'-deoxycytidine, 2',2'-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol. 1998;42:373-8 pubmed
    ..cytosine nucleoside analogs and if this resistance can be prevented by the CR deaminase inhibitor, 3,4,5,6-tetrahydrouridine (THU)...
  8. Bouffard D, Laliberte J, Momparler R. Kinetic studies on 2',2'-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol. 1993;45:1857-61 pubmed
    ..Diazepinone riboside was a more potent inhibitor than tetrahydrouridine using either CdR or dFdC as the substrate...
  9. Lavelle D, Vaitkus K, Ling Y, Ruiz M, Mahfouz R, Ng K, et al. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood. 2012;119:1240-7 pubmed publisher
    ..In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral ..

More Information


  1. Funamizu N, Okamoto A, Kamata Y, Misawa T, Uwagawa T, Gocho T, et al. Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?. Oncol Rep. 2010;23:471-5 pubmed
    ..Combination treatment based on expression of GEM metabolism-related gene may become an effective therapy in the future. ..
  2. Marsh J, Kreis W, Barile B, Akerman S, Schulman P, Allen S, et al. Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin. Cancer Chemother Pharmacol. 1993;31:481-4 pubmed
    ..a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and ..
  3. Kreis W, Budman D, Chan K, Allen S, Schulman P, Lichtman S, et al. Therapy of refractory/relapsed acute leukemia with cytosine arabinoside plus tetrahydrouridine (an inhibitor of cytidine deaminase)--a pilot study. Leukemia. 1991;5:991-8 pubmed
    ..Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight ..
  4. Aduma P, Gupta S, De Clercq E. Antiherpes virus activity and effect on deoxyribonucleoside triphosphate pools of (E)-5-(2-bromovinyl)-2'-deoxycytidine in combination with deaminase inhibitors. Antiviral Res. 1990;13:111-25 pubmed
    ..30 to 1.20 microM depending on the cell line used. In the presence of tetrahydrouridine or tetrahydrodeoxyuridine (H4dUrd), potency of BrVdCyd increased approximately two fold (ED50: 0...
  5. Aduma P, Gupta S, Stuart A, Tourigny G. Deoxyribonucleoside triphosphate pools of herpes simplex virus infected cells: the influence of selective antiherpes agents and the role of the deaminase pathway. Biochem Cell Biol. 1991;69:409-14 pubmed
    ..These results indicate that during viral replication the bulk of the thymidine nucleotides are derived from the dCyd/dCMP deaminase de novo pathway. ..
  6. Vande Voorde J, Sabuncuoğlu S, Noppen S, Hofer A, Ranjbarian F, Fieuws S, et al. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine. J Biol Chem. 2014;289:13054-65 pubmed publisher
    ..Indeed, the cytostatic activity of gemcitabine could be restored by the co-administration of tetrahydrouridine (a potent cytidine deaminase inhibitor)...
  7. Lawrence T, Davis M. Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine. Int J Radiat Oncol Biol Phys. 1989;16:1243-6 pubmed
    ..The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells...
  8. Parise R, Egorin M, Eiseman J, Joseph E, Covey J, Beumer J. Quantitative determination of the cytidine deaminase inhibitor tetrahydrouridine (THU) in mouse plasma by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2007;21:1991-7 pubmed
    ..3,4,5,6-Tetrahydrouridine (THU) is a potent inhibitor of CD, by acting as a transition-state analogue of its natural substrate ..
  9. Santos O, Perez L, Briggle T, Boothman D, Greer S. Radiation, pool size and incorporation studies in mice with 5-chloro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys. 1990;19:357-65 pubmed
    ..As shown in a previous study, tetrahydrouridine (H4U), a potent inhibitor of cytidine deaminase, can effectively inhibit the enzyme in the normal tissues of ..
  10. Hanauske A, Degen D, Marshall M, Hilsenbeck S, Grindey G, Von Hoff D. Activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human tumor colony forming units. Anticancer Drugs. 1992;3:143-6 pubmed
    ..The agent should be evaluated for Phase II clinical activity against those tumor types. ..
  11. Laliberte J, Marquez V, Momparler R. Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2'-deoxycytidine by human cytidine deaminase. Cancer Chemother Pharmacol. 1992;30:7-11 pubmed
    ..The inhibition constants for diazepinone riboside lay in the range of 5-15 nM, suggesting that this inhibitor could be an excellent candidate for use in combination chemotherapy with either ARA-C or 5-AZA-CdR in patients with leukemia. ..
  12. Wentworth D, Wolfenden R. On the interaction of 3,4,5,6-tetrahydrouridine with human liver cytidine deaminase. Biochemistry. 1975;14:5099-105 pubmed
    In contrast to the rapid inhibition of bacterial cytidine deaminase by 3,4,5,6-tetrahydrouridine, the onset of inhibition of the enzyme from human liver was found to be relatively slow...
  13. Montange D, Berard M, Demarchi M, Muret P, Piédoux S, Kantelip J, et al. An APCI LC-MS/MS method for routine determination of capecitabine and its metabolites in human plasma. J Mass Spectrom. 2010;45:670-7 pubmed publisher
    ..Interestingly, this method allows detection of TetraHydroUridine, an inhibitor of ex vivo degradation of metabolites, which is essential for the stability, the adequate ..
  14. Guo D, Myrdal P, Karlage K, O Connell S, Wissinger T, Tabibi S, et al. Stability of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in combination. AAPS PharmSciTech. 2010;11:247-52 pubmed publisher
    ..b>Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism...
  15. Grant S, Bhalla K, McCrady C. Effect of tetrahydrouridine and deoxytetrahydrouridine on the interaction between 2'-deoxycytidine and 1-beta-D-arabinofuranosylcytosine in human leukemia cells. Leuk Res. 1991;15:205-13 pubmed
    ..Co-administration of 1 mM tetrahydrouridine (THU) or 0...
  16. Vilpo J, Vilpo L. Biochemical mechanisms by which reutilization of DNA 5-methylcytosine is prevented in human cells. Mutat Res. 1991;256:29-35 pubmed
  17. Ebrahem Q, Mahfouz R, Ng K, Saunthararajah Y. High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects. Oncotarget. 2012;3:1137-45 pubmed
    ..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...
  18. Xiang T, Niemi R, Bummer P, Anderson B. Epimer interconversion, isomerization, and hydrolysis of tetrahydrouridine: implications for cytidine deaminase inhibition. J Pharm Sci. 2003;92:2027-39 pubmed
    b>Tetrahydrouridine (THU) is an inhibitor of cytidine deaminase (CDA), the enzyme responsible for the deactivation of ara-C and other cytidine analogues in vivo, and therefore is capable of improving the therapeutic efficacy of these ..
  19. Teh A, Kimura M, Yamamoto M, Tanaka N, Yamaguchi I, Kumasaka T. The 1.48 A resolution crystal structure of the homotetrameric cytidine deaminase from mouse. Biochemistry. 2006;45:7825-33 pubmed
    ..Here we present the crystal structure of mouse CDA (MmCDA), complexed with either tetrahydrouridine (THU), 3-deazauridine (DAU), or cytidine...
  20. Molokie R, Lavelle D, Gowhari M, Pacini M, Krauz L, Hassan J, et al. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study. PLoS Med. 2017;14:e1002382 pubmed publisher
    ..this first-in-human clinical trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates ..
  21. Norton J, Matsuo H, Sturla S. Synthesis of deoxytetrahydrouridine. J Org Chem. 2009;74:2221-3 pubmed publisher
    ..Evidence was obtained for formation of a methoxy-substituted analogue during purification. By this strategy, dTHU of >95% purity can be obtained in 40% yield on a 150 mg scale. ..
  22. Besnard T, Renée N, Etienne Grimaldi M, Francois E, Milano G. Optimized blood sampling with cytidine deaminase inhibitor for improved analysis of capecitabine metabolites. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;870:117-20 pubmed publisher
    ..We thus examined the impact of the addition of a CDA inhibitor (tetrahydrouridine (THU) 1 microM final) in blood...
  23. Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014;57:2582-8 pubmed publisher
    Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA)...
  24. Carnrot C, Wehelie R, Eriksson S, Bölske G, Wang L. Molecular characterization of thymidine kinase from Ureaplasma urealyticum: nucleoside analogues as potent inhibitors of mycoplasma growth. Mol Microbiol. 2003;50:771-80 pubmed
  25. Riva C, Barra Y, Carcassonne Y, Cano J, Rustum Y. Effect of tetrahydrouridine on metabolism and transport of 1-beta-D-arabinofuranosylcytosine in human cells. Chemotherapy. 1992;38:358-66 pubmed
    ..The present study was undertaken to determine the effect of tetrahydrouridine (THU; a potent inhibitor of cytidine deaminase) on ara-C transport and metabolism in human cells...
  26. Aduma P, Gupta S, Stuart A, Tourigny G. Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2'-deoxycytidine: modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine. Antiviral Res. 1991;15:301-13 pubmed
    ..06 mM) in combination with dGuo (100 microM), resulted in an increase of the dCTP pool and a marked fall in the dTTP and dGTP pool. The possible mechanisms for potentiation of MMdCyd activity by dGuo and H4dUrd are discussed. ..
  27. Hoover E, Zeidner N, Perigo N, Quackenbush S, Strobel J, Hill D, et al. Feline leukemia virus-induced immunodeficiency syndrome in cats as a model for evaluation of antiretroviral therapy. Intervirology. 1989;30 Suppl 1:12-25 pubmed
    ..The FeLV model, therefore, can be used to assess rapidly experimental single agent or combined antiviral therapies for persistent retrovirus infection and disease. ..
  28. Greer S, Schwade J, Marion H. Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation. Int J Radiat Oncol Biol Phys. 1995;32:1059-69 pubmed
    ..12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2'-deoxycytidine (CldC) and biomodulators of its metabolism: N-(Phosphonacetyl)-L-aspartate (PALA), tetrahydrouridine and 5-fluoro-2'-deoxycytidine (FdC).
  29. Peters G, van Groeningen C, Laurensse E, Lankelma J, Leyva A, Pinedo H. Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites. Cancer Chemother Pharmacol. 1987;20:101-8 pubmed
  30. Avramis V, Powell W. Pharmacology of combination chemotherapy of cytosine arabinoside (ara-C) and uracil arabinoside (ara-U) or tetrahydrouridine (THU) against murine leukemia L1210/0 in tumor-bearing mice. Cancer Invest. 1987;5:293-9 pubmed
    ..b>Tetrahydrouridine (THU) and the deamination product, uracil arabinoside (ara-U) are potent inhibitors of Cyt DA...
  31. Heinemann V, Plunkett W. Modulation of deoxynucleotide metabolism by the deoxycytidylate deaminase inhibitor 3,4,5,6-tetrahydrodeoxyuridine. Biochem Pharmacol. 1989;38:4115-21 pubmed
    ..b>Tetrahydrouridine, which inhibits deoxycytidine deaminase exclusively, had no effect on nucleotide pools...
  32. Zeidner N, Strobel J, Perigo N, Hill D, Mullins J, Hoover E. Treatment of FeLV-induced immunodeficiency syndrome (FeLV-FAIDS) with controlled release capsular implantation of 2',3'-dideoxycytidine. Antiviral Res. 1989;11:147-60 pubmed
    ..These values could not be augmented with high levels of the deaminase blocker tetrahydrouridine administered prior to or concurrently with ddC...
  33. Greer S, Alvarez M, Mas M, Wozniak C, Arnold D, Knapinska A, et al. Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice. Int J Radiat Oncol Biol Phys. 2001;51:791-806 pubmed
    ..in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H4U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP ..
  34. Funamizu N, Lacy C, Fujita K, Furukawa K, Misawa T, Yanaga K, et al. Tetrahydrouridine inhibits cell proliferation through cell cycle regulation regardless of cytidine deaminase expression levels. PLoS ONE. 2012;7:e37424 pubmed publisher
    b>Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance...
  35. Santos O, Pant K, Blank E, Ceriani R. 5-Iododeoxyuridine increases the efficacy of the radioimmunotherapy of human tumors growing in nude mice. J Nucl Med. 1992;33:1530-4 pubmed
    ..5-Iododeoxyuridine was administered with N-(phosphonacetyl)-L-aspartic acid and 5-fluoro-deoxycytidine plus tetrahydrouridine. This drug treatment was combined with radioimmunotherapy using 131I conjugated to a monoclonal antibody, ..
  36. Yusa K, Oh hara T, Tsukahara S, Tsuruo T. Human immunodeficiency virus type 1 induces 1-beta-D-arabinofuranosylcytosine resistance in human H9 cell line. J Biol Chem. 1992;267:16848-50 pubmed
    ..in the infected H9 cells occurred after treatment with the inhibitor of cytidine deaminase, 3,4,5,6-tetrahydrouridine. The understanding of these cellular alterations in drug sensitivity may facilitate the development of ..
  37. Morfouace M, Nimmervoll B, Boulos N, Patel Y, Shelat A, Freeman B, et al. Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. J Neurooncol. 2016;126:225-34 pubmed publisher
    ..Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models...
  38. Dong M, Dedon P. Relatively small increases in the steady-state levels of nucleobase deamination products in DNA from human TK6 cells exposed to toxic levels of nitric oxide. Chem Res Toxicol. 2006;19:50-7 pubmed
    ..This could result from limited nitrosative chemistry in nuclear DNA in cells exposed to NO or high levels of formation balanced by rapid repair of nucleobase deamination lesions in DNA. ..
  39. Yusa K, Oh hara T, Tsuruo T. Induction of resistance to 1-beta-D-arabinofuranosylcytosine in human H9 cell line by simian immunodeficiency virus. Biochem Biophys Res Commun. 1995;206:486-91 pubmed
    ..A competitive inhibitor of cytidine deaminase, 3, 4, 5, 6-tetrahydrouridine (THU), at 100 microM reversed Ara-C resistance in the infected cells...
  40. Hale J, Bigelow J, Mathews L, McCormack J. Analytical and pharmacokinetic studies with 5-chloro-2'-deoxycytidine. Biochem Pharmacol. 2002;64:1493-502 pubmed
    ..properties of CDC and the disposition of the drug, both alone and in the presence of the metabolic modulator tetrahydrouridine (THU), a cytidine deaminase inhibitor...