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[PMID]:28880867
[Au] Autor:Molokie R; Lavelle D; Gowhari M; Pacini M; Krauz L; Hassan J; Ibanez V; Ruiz MA; Ng KP; Woost P; Radivoyevitch T; Pacelli D; Fada S; Rump M; Hsieh M; Tisdale JF; Jacobberger J; Phelps M; Engel JD; Saraf S; Hsu LL; Gordeuk V; DeSimone J; Saunthararajah Y
[Ad] Endereço:Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, Illinois, United States of America.
[Ti] Título:Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.
[So] Source:PLoS Med;14(9):e1002382, 2017 Sep.
[Is] ISSN:1549-1676
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To pharmacologically re-induce HbF by DNMT1 inhibition, 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 decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability. Oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow-up. The primary endpoint was ≥ grade 3 non-hematologic toxicity. This endpoint was not triggered, and adverse events (AEs) were not significantly different in THU-decitabine-versus placebo-treated patients. At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and remained elevated for several hours. This dose decreased DNMT1 protein in peripheral blood mononuclear cells by >75% and repetitive element CpG methylation by approximately 10%, and increased HbF by 4%-9% (P < 0.001), doubling fetal hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total RBCs. Total hemoglobin increased by 1.2-1.9 g/dL (P = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved. As expected with non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds. As an early phase study, limitations include small patient numbers at each dose level and narrow capacity to evaluate clinical benefits. CONCLUSION: Administration of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical benefits and potential harms not identified to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01685515.
[Mh] Termos MeSH primário: Anemia Falciforme/tratamento farmacológico
Azacitidina/análogos & derivados
Inibidores Enzimáticos/administração & dosagem
Epigênese Genética/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Tetra-Hidrouridina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Anemia Falciforme/genética
Azacitidina/administração & dosagem
Azacitidina/farmacologia
Quimioterapia Combinada
Inibidores Enzimáticos/farmacologia
Feminino
Hemoglobina Fetal/efeitos dos fármacos
Inativação Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Meia-Idade
Tetra-Hidrouridina/farmacologia
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 18771-50-1 (Tetrahydrouridine); 776B62CQ27 (decitabine); 9034-63-3 (Fetal Hemoglobin); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170917
[Lr] Data última revisão:
170917
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pmed.1002382


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[PMID]:28318037
[Au] Autor:Lopez-Gomez C; Levy RJ; Sanchez-Quintero MJ; Juanola-Falgarona M; Barca E; Garcia-Diaz B; Tadesse S; Garone C; Hirano M
[Ad] Endereço:Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY.
[Ti] Título:Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.
[So] Source:Ann Neurol;81(5):641-652, 2017 May.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2 ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. METHODS: To test these hypotheses, we assessed two therapies in Tk2 mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. RESULTS: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2 animals compared to dCMP+dTMP. INTERPRETATION: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652.
[Mh] Termos MeSH primário: Antimetabólitos/farmacologia
Desoxicitidina Monofosfato/farmacologia
Erros Inatos do Metabolismo/tratamento farmacológico
Doenças Mitocondriais/tratamento farmacológico
Tetra-Hidrouridina/farmacologia
Timidina Quinase/deficiência
Timidina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antimetabólitos/administração & dosagem
DNA Mitocondrial/efeitos dos fármacos
Desoxicitidina Monofosfato/administração & dosagem
Modelos Animais de Doenças
Quimioterapia Combinada
Erros Inatos do Metabolismo/enzimologia
Camundongos
Camundongos Transgênicos
Doenças Mitocondriais/enzimologia
Tetra-Hidrouridina/administração & dosagem
Timidina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites); 0 (DNA, Mitochondrial); 1032-65-1 (Deoxycytidine Monophosphate); 18771-50-1 (Tetrahydrouridine); EC 2.7.1.- (thymidine kinase 2); EC 2.7.1.21 (Thymidine Kinase); VC2W18DGKR (Thymidine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170321
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24922


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[PMID]:27454087
[Au] Autor:Holleran JL; Eiseman JL; Parise RA; Kummar S; Beumer JH
[Ad] Endereço:Cancer Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States.
[Ti] Título:LC-MS/MS assay for the quantitation of FdCyd and its metabolites FdUrd and FU in human plasma.
[So] Source:J Pharm Biomed Anal;129:359-366, 2016 Sep 10.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The hypomethylating agent 5-fluoro-2'-deoxycytidine (FdCyd, NSC 48006) is being evaluated clinically both via the intravenous route and via the oral route in combination with 3,4,5,6-tetrahydrouridine (THU), a potent inhibitor of FdCyd catabolism. To determine the pharmacokinetics of FdCyd and downstream metabolites, we developed and validated an LC-MS/MS assay for the quantitation of FdCyd, 5-fluoro-2'-deoxyuridine (FdUrd), and 5-fluorouracil (FU) in 0.2mL human plasma. After acetonitrile protein precipitation, the sample was split and separate chromatography was achieved for FdCyd with a Synergi Polar-RP column and for FdUrd and FU with a Shodex Asahipak NH2P-50 2D column. Gradients of 0.1% acetic acid in acetonitrile and water were used. Detection with a Quattromicro quadrupole mass spectrometer with electrospray ionization in positive-ion (FdCyd) or negative-ion (FdUrd and FU) multiple reaction monitoring (MRM) mode. The assay was linear from 5 to 3000ng/mL for all three analytes and proved to be accurate (96.7-105.5%) and precise (<8.1%CV), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring FdCyd and metabolites FdUrd and FU in plasma from a patient who was administered 120mg PO FdCyd 30min after 3000mg THU. Our LC-MS/MS assay will be an essential tool to further define the pharmacology of FdCyd in ongoing and future studies.
[Mh] Termos MeSH primário: Desoxiuridina/análogos & derivados
Fluoruracila/sangue
Fluoruracila/química
Plasma/química
[Mh] Termos MeSH secundário: Bioensaio/métodos
Cromatografia Líquida/métodos
Desoxiuridina/sangue
Desoxiuridina/química
Desoxiuridina/farmacocinética
Seres Humanos
Espectrometria de Massas em Tandem/métodos
Tetra-Hidrouridina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-fluoro-2'-deoxyuridine); 18771-50-1 (Tetrahydrouridine); U3P01618RT (Fluorouracil); W78I7AY22C (Deoxyuridine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170910
[Lr] Data última revisão:
170910
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160726
[St] Status:MEDLINE


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[PMID]:26518542
[Au] Autor:Morfouace M; Nimmervoll B; Boulos N; Patel YT; Shelat A; Freeman BB; Robinson GW; Wright K; Gajjar A; Stewart CF; Gilbertson RJ; Roussel MF
[Ad] Endereço:Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
[Ti] Título:Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.
[So] Source:J Neurooncol;126(2):225-34, 2016 Jan.
[Is] ISSN:1573-7373
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. 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. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Neoplasias Encefálicas/tratamento farmacológico
Encéfalo/efeitos dos fármacos
Desoxicitidina/análogos & derivados
Modelos Animais de Doenças
Avaliação Pré-Clínica de Medicamentos/métodos
Tetra-Hidrouridina/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/sangue
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Desoxicitidina/administração & dosagem
Desoxicitidina/sangue
Desoxicitidina/farmacocinética
Desoxicitidina/uso terapêutico
Relação Dose-Resposta a Droga
Epigênese Genética/efeitos dos fármacos
Camundongos
Camundongos Nus
Tetra-Hidrouridina/sangue
Tetra-Hidrouridina/farmacocinética
Tetra-Hidrouridina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0W860991D6 (Deoxycytidine); 18771-50-1 (Tetrahydrouridine); KUA4693H5W (5-fluoro-2'-deoxycytidine)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151101
[St] Status:MEDLINE
[do] DOI:10.1007/s11060-015-1965-0


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[PMID]:26321472
[Au] Autor:Holleran JL; Beumer JH; McCormick DL; Johnson WD; Newman EM; Doroshow JH; Kummar S; Covey JM; Davis M; Eiseman JL
[Ad] Endereço:Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
[Ti] Título:Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans.
[So] Source:Cancer Chemother Pharmacol;76(4):803-11, 2015 Oct.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: 5-Fluoro-2'-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). METHODS: Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability. RESULTS: After IV FdCyd and THU administration, FdCyd C(max) and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %). CONCLUSION: Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1 to 24 %. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times three at the beginning of the first and second weeks of a 28-day cycle.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/farmacocinética
Citidina Desaminase/antagonistas & inibidores
Desoxicitidina/análogos & derivados
Inibidores Enzimáticos/farmacocinética
Tetra-Hidrouridina/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Antimetabólitos Antineoplásicos/administração & dosagem
Antimetabólitos Antineoplásicos/sangue
Disponibilidade Biológica
Biotransformação
Estudos de Coortes
Desoxicitidina/administração & dosagem
Desoxicitidina/sangue
Desoxicitidina/farmacocinética
Relação Dose-Resposta a Droga
Combinação de Medicamentos
Avaliação Pré-Clínica de Medicamentos
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/sangue
Feminino
Meia-Vida
Seres Humanos
Infusões Intravenosas
Macaca fascicularis
Masculino
Taxa de Depuração Metabólica
Projetos Piloto
Tetra-Hidrouridina/administração & dosagem
Tetra-Hidrouridina/sangue
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Drug Combinations); 0 (Enzyme Inhibitors); 0W860991D6 (Deoxycytidine); 18771-50-1 (Tetrahydrouridine); EC 3.5.4.5 (Cytidine Deaminase); KUA4693H5W (5-fluoro-2'-deoxycytidine)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150901
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-015-2857-x


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[PMID]:25641274
[Au] Autor:Mano Y; Sakamaki K; Ueno T; Kita K; Ishii T; Hotta K; Kusano K
[Ad] Endereço:Drug Metabolism and Pharmacokinetics, Biopharmaceutical Assessment Core Function Unit, Eisai Co. Ltd, 1-3, 5-chome, Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
[Ti] Título:Validation of a hydrophilic interaction ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of gemcitabine in human plasma with tetrahydrouridine.
[So] Source:Biomed Chromatogr;29(9):1343-9, 2015 Sep.
[Is] ISSN:1099-0801
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A simple and reproducible bioanalytical method for the determination of gemcitabine in human plasma treated with tetrahydrouridine (THU) was developed and validated using a hydrophilic interaction ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). To prevent deamination of gemcitabine, blood was treated with THU, and the plasma samples obtained after centrifugation were used in this study. Gemcitabine and gemcitabine-(13)C, (15)N2 used as an internal standard, were extracted from human plasma treated with THU using a 96-well Hybrid SPE-Precipitation plate. Extracts were chromatographed on a hydrophilic interaction chromatography column with isocratic elution. Detection was performed using Quattro Premier with positive electrospray ionization multiple reaction monitoring mode. The standard curve ranged from 10 to 10,000 ng/mL without carryover. No significant interferences were detected in blank plasma and no interferences by 2'-2'-difluoro-2'-deoxyuridine, a metabolite of gemcitabine. Accuracy and precision in the intra-batch reproducibility study using quality control samples with three THU levels did not exceed ±5.4 and 7.3%, respectively, and the inter-batch reproducibility results also met the criteria. Stability of gemcitabine was ensured in whole blood and plasma as well as stability of THU in solutions. The UPLC-MS/MS method developed was successfully validated and can be applied for gemcitabine bioanalysis in clinical studies.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão/métodos
Desoxicitidina/análogos & derivados
Espectrometria de Massas em Tandem/métodos
Tetra-Hidrouridina/química
[Mh] Termos MeSH secundário: Cromatografia Líquida de Alta Pressão/instrumentação
Desoxicitidina/sangue
Desoxicitidina/química
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0W860991D6 (Deoxycytidine); 18771-50-1 (Tetrahydrouridine); B76N6SBZ8R (gemcitabine)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150817
[Lr] Data última revisão:
150817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150203
[St] Status:MEDLINE
[do] DOI:10.1002/bmc.3429


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[PMID]:25567350
[Au] Autor:Newman EM; Morgan RJ; Kummar S; Beumer JH; Blanchard MS; Ruel C; El-Khoueiry AB; Carroll MI; Hou JM; Li C; Lenz HJ; Eiseman JL; Doroshow JH
[Ad] Endereço:Department of Molecular Pharmacology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA, enewman@coh.org.
[Ti] Título:A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine.
[So] Source:Cancer Chemother Pharmacol;75(3):537-46, 2015 Mar.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2'-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU). METHODS: FdCyd + THU were administered by 3 h IV infusion on days 1-5 every 3 weeks, or days 1-5 and 8-12 every 4 weeks. FdCyd was administered IV with a fixed 350 mg/m(2)/day dose of THU to inhibit deamination of FdCyd. Pharmacokinetics of FdCyd, downstream metabolites and THU were assessed by LC-MS/MS. RBC γ-globin expression was evaluated as a pharmacodynamics biomarker. RESULTS: Patients were enrolled on the 3-week schedule at doses up to 80 mg/m(2)/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m(2)/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd ≥40 mg/m(2)/day produced peak plasma concentrations >1 µM. Although there was inter-patient variability, γ-globin mRNA increased during the first two treatment cycles. One refractory breast cancer patient experienced a partial response (PR) of >90 % decrease in tumor size, lasting over a year. CONCLUSIONS: The MTD was established at 134 mg/m(2) FdCyd + 350 mg/m(2) THU days 1-5 and 8-12 every 4 weeks. Based on toxicities observed over multiple cycles, good plasma exposures, and the sustained PR observed at 67 mg/m(2)/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m(2)/day FdCyd with 350 mg/m(2)/day THU.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores
Neoplasias/tratamento farmacológico
gama-Globulinas/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Cromatografia Líquida
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Infusões Intravenosas
Masculino
Dose Máxima Tolerável
Meia-Idade
Neoplasias/patologia
Espectrometria de Massas em Tandem
Tetra-Hidrouridina/administração & dosagem
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (gamma-Globulins); 0W860991D6 (Deoxycytidine); 18771-50-1 (Tetrahydrouridine); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); KUA4693H5W (5-fluoro-2'-deoxycytidine)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150109
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-014-2674-7


  8 / 113 MEDLINE  
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[PMID]:24668817
[Au] Autor:Vande Voorde J; Sabuncuoglu S; Noppen S; Hofer A; Ranjbarian F; Fieuws S; Balzarini J; Liekens S
[Ad] Endereço:From the Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, blok x-bus 1030, B-3000 Leuven, Belgium.
[Ti] Título:Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine.
[So] Source:J Biol Chem;289(19):13054-65, 2014 May 09.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The intracellular metabolism and cytostatic activity of the anticancer drug gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) was severely compromised in Mycoplasma hyorhinis-infected tumor cell cultures. Pronounced deamination of dFdC to its less cytostatic metabolite 2',2'-difluoro-2'-deoxyuridine was observed, both in cell extracts and spent culture medium (i.e. tumor cell-free but mycoplasma-containing) of mycoplasma-infected tumor cells. This indicates that the decreased antiproliferative activity of dFdC in such cells is attributed to a mycoplasma cytidine deaminase causing rapid drug catabolism. Indeed, the cytostatic activity of gemcitabine could be restored by the co-administration of tetrahydrouridine (a potent cytidine deaminase inhibitor). Additionally, mycoplasma-derived pyrimidine nucleoside phosphorylase (PyNP) activity indirectly potentiated deamination of dFdC: the natural pyrimidine nucleosides uridine, 2'-deoxyuridine and thymidine inhibited mycoplasma-associated dFdC deamination but were efficiently catabolized (removed) by mycoplasma PyNP. The markedly lower anabolism and related cytostatic activity of dFdC in mycoplasma-infected tumor cells was therefore also (partially) restored by a specific TP/PyNP inhibitor (TPI), or by exogenous thymidine. Consequently, no effect on the cytostatic activity of dFdC was observed in tumor cell cultures infected with a PyNP-deficient Mycoplasma pneumoniae strain. Because it has been reported that some commensal mycoplasma species (including M. hyorhinis) preferentially colonize tumor tissue in cancer patients, our findings suggest that the presence of mycoplasmas in the tumor microenvironment could be a limiting factor for the anticancer efficiency of dFdC-based chemotherapy. Accordingly, a significantly decreased antitumor effect of dFdC was observed in mice bearing M. hyorhinis-infected murine mammary FM3A tumors compared with uninfected tumors.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos
Proteínas de Bactérias/metabolismo
Neoplasias da Mama
Desoxicitidina/análogos & derivados
Neoplasias Mamárias Experimentais
Infecções por Mycoplasma/enzimologia
Mycoplasma hyorhinis/enzimologia
Pirimidina Fosforilases/metabolismo
[Mh] Termos MeSH secundário: Animais
Antimetabólitos Antineoplásicos/farmacocinética
Antimetabólitos Antineoplásicos/farmacologia
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Neoplasias da Mama/microbiologia
Linhagem Celular Tumoral
Desoxicitidina/farmacocinética
Desoxicitidina/farmacologia
Feminino
Seres Humanos
Neoplasias Mamárias Experimentais/tratamento farmacológico
Neoplasias Mamárias Experimentais/metabolismo
Neoplasias Mamárias Experimentais/microbiologia
Camundongos
Tetra-Hidrouridina/farmacocinética
Tetra-Hidrouridina/farmacologia
Timidina/metabolismo
Microambiente Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Bacterial Proteins); 0W860991D6 (Deoxycytidine); 18771-50-1 (Tetrahydrouridine); B76N6SBZ8R (gemcitabine); EC 2.4.2.- (Pyrimidine Phosphorylases); VC2W18DGKR (Thymidine)
[Em] Mês de entrada:1406
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140327
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.558924


  9 / 113 MEDLINE  
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[PMID]:24639139
[Au] Autor:Terse P; Engelke K; Chan K; Ling Y; Sharpnack D; Saunthararajah Y; Covey JM
[Ad] Endereço:Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Bethesda, MD, USA. Email: tersep@mail.nih.gov.
[Ti] Título:Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.
[So] Source:Int J Toxicol;33(2):75-85, 2014 Mar-Apr.
[Is] ISSN:1092-874X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Decitabine (5-aza-2'-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and ß-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼ 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.
[Mh] Termos MeSH primário: Antimetabólitos/toxicidade
Azacitidina/análogos & derivados
Tetra-Hidrouridina/toxicidade
[Mh] Termos MeSH secundário: Animais
Antimetabólitos Antineoplásicos
Azacitidina/toxicidade
Contagem de Células Sanguíneas
Peso Corporal/efeitos dos fármacos
Células da Medula Óssea/efeitos dos fármacos
Ingestão de Alimentos/efeitos dos fármacos
Feminino
Masculino
Camundongos
Testes para Micronúcleos
Farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Antimetabolites, Antineoplastic); 18771-50-1 (Tetrahydrouridine); 776B62CQ27 (decitabine); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1411
[Cu] Atualização por classe:161203
[Lr] Data última revisão:
161203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140319
[St] Status:MEDLINE
[do] DOI:10.1177/1091581814524994


  10 / 113 MEDLINE  
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[PMID]:24520856
[Au] Autor:Ferraris D; Duvall B; Delahanty G; Mistry B; Alt J; Rojas C; Rowbottom C; Sanders K; Schuck E; Huang KC; Redkar S; Slusher BB; Tsukamoto T
[Ad] Endereço:Eisai Inc. , Baltimore, Maryland 21224, United States.
[Ti] Título:Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.
[So] Source:J Med Chem;57(6):2582-8, 2014 Mar 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.
[Mh] Termos MeSH primário: Citidina Desaminase/antagonistas & inibidores
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/farmacologia
Tetra-Hidrouridina/análogos & derivados
Tetra-Hidrouridina/síntese química
[Mh] Termos MeSH secundário: Animais
Azacitidina/análogos & derivados
Azacitidina/farmacologia
Disponibilidade Biológica
Desenho de Drogas
Estabilidade de Medicamentos
Inibidores Enzimáticos/farmacocinética
Potenciais Pós-Sinápticos Excitadores
Flúor
Suco Gástrico/química
Macaca mulatta
Modelos Moleculares
Conformação Molecular
Relação Estrutura-Atividade
Tetra-Hidrouridina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 18771-50-1 (Tetrahydrouridine); 284SYP0193 (Fluorine); 776B62CQ27 (decitabine); EC 3.5.4.5 (Cytidine Deaminase); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:140327
[Lr] Data última revisão:
140327
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140214
[St] Status:MEDLINE
[do] DOI:10.1021/jm401856k



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