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[PMID]:27943397
[Au] Autor:Wong DR; Coenen MJ; Derijks LJ; Vermeulen SH; van Marrewijk CJ; Klungel OH; Scheffer H; Franke B; Guchelaar HJ; de Jong DJ; Engels LG; Verbeek AL; Hooymans PM; TOPIC Recruitment Team
[Ad] Endereço:Sittard-Geleen, The Netherlands.
[Ti] Título:Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.
[So] Source:Aliment Pharmacol Ther;45(3):391-402, 2017 Feb.
[Is] ISSN:1365-2036
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. AIM: To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. METHODS: The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. RESULTS: Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). CONCLUSIONS: In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure.
[Mh] Termos MeSH primário: Azatioprina/efeitos adversos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico
Doenças Inflamatórias Intestinais/diagnóstico
Doenças Inflamatórias Intestinais/tratamento farmacológico
Mercaptopurina/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Doença Hepática Induzida por Substâncias e Drogas/genética
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Estudos de Coortes
Diagnóstico Precoce
Feminino
Genótipo
Seres Humanos
Doenças Inflamatórias Intestinais/genética
Doenças Inflamatórias Intestinais/metabolismo
Masculino
Mercaptopurina/análogos & derivados
Metiltransferases/metabolismo
Meia-Idade
Prognóstico
Fatores de Risco
Tioinosina/análogos & derivados
Tioinosina/metabolismo
Tionucleotídeos/metabolismo
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Thionucleotides); 46S541971T (Thioinosine); 6V404DV25O (6-methylthiopurine); 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate); E7WED276I5 (Mercaptopurine); EC 2.1.1.- (Methyltransferases); EC 2.1.1.67 (thiopurine methyltransferase); MRK240IY2L (Azathioprine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE
[do] DOI:10.1111/apt.13879


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[PMID]:27402913
[Au] Autor:Wong DR; Coenen MJ; Vermeulen SH; Derijks LJ; van Marrewijk CJ; Klungel OH; Scheffer H; Franke B; Guchelaar HJ; de Jong DJ; Engels LG; Verbeek AL; Hooymans PM; TOPIC recruitment team
[Ad] Endereço:Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands d.wong@zuyderland.nl.
[Ti] Título:Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.
[So] Source:J Crohns Colitis;11(2):175-184, 2017 Feb.
[Is] ISSN:1876-4479
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 10 /L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 10 erythrocytes and 3525 pmol/8 × 10 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.
[Mh] Termos MeSH primário: Azatioprina
Nucleotídeos de Guanina/análise
Doenças Inflamatórias Intestinais
Leucopenia
Mercaptopurina
Tioinosina/análogos & derivados
Tionucleotídeos/análise
[Mh] Termos MeSH secundário: Adulto
Idoso
Azatioprina/administração & dosagem
Azatioprina/efeitos adversos
Azatioprina/farmacocinética
Hipersensibilidade a Drogas/diagnóstico
Interações Medicamentosas
Feminino
Seres Humanos
Imunossupressores/administração & dosagem
Imunossupressores/efeitos adversos
Imunossupressores/farmacocinética
Doenças Inflamatórias Intestinais/tratamento farmacológico
Doenças Inflamatórias Intestinais/metabolismo
Contagem de Leucócitos/métodos
Leucopenia/induzido quimicamente
Leucopenia/diagnóstico
Leucopenia/metabolismo
Leucopenia/prevenção & controle
Masculino
Mercaptopurina/administração & dosagem
Mercaptopurina/efeitos adversos
Mercaptopurina/farmacocinética
Meia-Idade
Países Baixos
Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico
Reprodutibilidade dos Testes
Medição de Risco/métodos
Tioinosina/análise
Fator de Necrose Tumoral alfa/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Guanine Nucleotides); 0 (Immunosuppressive Agents); 0 (Thionucleotides); 0 (Tumor Necrosis Factor-alpha); 15867-02-4 (6-thioguanylic acid); 46S541971T (Thioinosine); 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate); E7WED276I5 (Mercaptopurine); MRK240IY2L (Azathioprine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160713
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1093/ecco-jcc/jjw130


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[PMID]:27906634
[Au] Autor:Zafar M; Naydenova Z; Coe IR
[Ad] Endereço:a Department of Chemistry and Biology , Ryerson University , Toronto , Canada.
[Ti] Título:Extended exposure to substrate regulates the human equilibrative nucleoside transporter 1 (hENT1).
[So] Source:Nucleosides Nucleotides Nucleic Acids;35(10-12):631-642, 2016 Dec.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human equilibrative nucleoside transporter 1 (hENT1) is a major route of entry of nucleosides and nucleoside analog drugs. The regulation of hENT1 is poorly understood in spite of its clinical importance as a drug transporter. Immunofluorescence microscopy and fluorescence-activated cell sorting suggested that cytidine pre-treatment (40 µM, 6 h) promotes hENT1 internalization in a way that does not affect either hENT1-mediated nucleoside uptake or gemcitabine-induced cytotoxicity. The Scatchard plot analyses of our NBTI binding data support previous speculations that hENT1 proteins exist as two sub-populations, and suggest that cytidine pre-treatment leads to the internalization of one population.
[Mh] Termos MeSH primário: Transportador Equilibrativo 1 de Nucleosídeo/fisiologia
[Mh] Termos MeSH secundário: Antimetabólitos Antineoplásicos/farmacologia
Sítios de Ligação
Citidina/farmacologia
Desoxicitidina/análogos & derivados
Desoxicitidina/farmacologia
Células HEK293
Seres Humanos
Transporte Proteico
Tioinosina/análogos & derivados
Tioinosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Equilibrative Nucleoside Transporter 1); 0 (SLC29A1 protein, human); 0W860991D6 (Deoxycytidine); 46S541971T (Thioinosine); 5CSZ8459RP (Cytidine); B76N6SBZ8R (gemcitabine); GV1L2DZM2Z (4-nitrobenzylthioinosine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE


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[PMID]:27760406
[Au] Autor:Sabnis HS; Bradley HL; Tripathi S; Yu WM; Tse W; Qu CK; Bunting KD
[Ad] Endereço:Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
[Ti] Título:Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine.
[So] Source:Leuk Res;50:132-140, 2016 Nov.
[Is] ISSN:1873-5835
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10-25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60-70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6-BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death.
[Mh] Termos MeSH primário: Morte Celular/efeitos dos fármacos
Leucemia Mieloide Aguda/tratamento farmacológico
Metformina/uso terapêutico
Tioinosina/análogos & derivados
[Mh] Termos MeSH secundário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Linhagem Celular Tumoral
Sinergismo Farmacológico
Sangue Fetal/citologia
Glicólise/efeitos dos fármacos
Seres Humanos
Sequências Repetidas Invertidas
Leucemia Mieloide Aguda/genética
Fator de Transcrição STAT5/antagonistas & inibidores
Tioinosina/uso terapêutico
Tirosina Quinase 3 Semelhante a fms/genética
Tirosina Quinase 3 Semelhante a fms/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-benzylthioinosine); 0 (STAT5 Transcription Factor); 46S541971T (Thioinosine); 9100L32L2N (Metformin); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE


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[PMID]:27383770
[Au] Autor:Queiroga CS; Alves RM; Conde SV; Alves PM; Vieira HL
[Ad] Endereço:CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, Lisboa 1169-056, Portugal.
[Ti] Título:Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.
[So] Source:J Cell Sci;129(16):3178-88, 2016 Aug 15.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling.
[Mh] Termos MeSH primário: Astrócitos/metabolismo
Monóxido de Carbono/farmacologia
Neuroproteção/efeitos dos fármacos
Comunicação Parácrina/efeitos dos fármacos
Receptores Purinérgicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenosina/farmacologia
Trifosfato de Adenosina/análogos & derivados
Trifosfato de Adenosina/metabolismo
Trifosfato de Adenosina/farmacologia
Animais
Apoptose/efeitos dos fármacos
Astrócitos/efeitos dos fármacos
Técnicas de Cocultura
Cisteína/metabolismo
Espaço Extracelular/metabolismo
Inativação Gênica/efeitos dos fármacos
Ácido Glicirretínico/análogos & derivados
Ácido Glicirretínico/farmacologia
Camundongos Endogâmicos C57BL
Modelos Biológicos
Neurônios/citologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Pirimidinas/farmacologia
Receptor trkB/metabolismo
Receptores A2 de Adenosina/metabolismo
Serina/metabolismo
Suramina/farmacologia
Tioinosina/análogos & derivados
Tioinosina/farmacologia
Triazóis/farmacologia
Xantinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine); 0 (6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP); 0 (Pyrimidines); 0 (Receptors, Adenosine A2); 0 (Receptors, Purinergic); 0 (Triazoles); 0 (Xanthines); 1449-05-4 (18alpha-glycyrrhetinic acid); 452VLY9402 (Serine); 46S541971T (Thioinosine); 6032D45BEM (Suramin); 7U1EE4V452 (Carbon Monoxide); 8L70Q75FXE (Adenosine Triphosphate); 9PTP4FOI9E (1,3-dipropyl-8-cyclopentylxanthine); EC 2.7.10.1 (Receptor, trkB); GV1L2DZM2Z (4-nitrobenzylthioinosine); K72T3FS567 (Adenosine); K848JZ4886 (Cysteine); NYX13NT29D (alpha,beta-methyleneadenosine 5'-triphosphate); P540XA09DR (Glycyrrhetinic Acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160708
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.187260


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[PMID]:26876431
[Au] Autor:Moon W; Loftus EV
[Ad] Endereço:Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
[Ti] Título:Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease.
[So] Source:Aliment Pharmacol Ther;43(8):863-883, 2016 Apr.
[Is] ISSN:1365-2036
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Azathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount. AIM: To provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in IBD. METHODS: A literature search up to July 2015 was performed in PubMed using a combination of relevant MeSH terms. RESULTS: Pre-treatment thiopurine S-methyltransferase typing plus measurement of 6-tioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3-7%, and to improve efficacy by 15-30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association between AOX activity and AZA dose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate-linked moiety X-type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S-transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice. CONCLUSIONS: Measurement of thiopurine-related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.
[Mh] Termos MeSH primário: Doenças Inflamatórias Intestinais/tratamento farmacológico
Farmacogenética
[Mh] Termos MeSH secundário: Azatioprina/uso terapêutico
Seres Humanos
Mercaptopurina/análogos & derivados
Mercaptopurina/uso terapêutico
Metiltransferases/metabolismo
Tioinosina/análogos & derivados
Tioinosina/metabolismo
Tionucleotídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Thionucleotides); 46S541971T (Thioinosine); 6V404DV25O (6-methylthiopurine); 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate); E7WED276I5 (Mercaptopurine); EC 2.1.1.- (Methyltransferases); EC 2.1.1.67 (thiopurine methyltransferase); MRK240IY2L (Azathioprine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160216
[St] Status:MEDLINE
[do] DOI:10.1111/apt.13559


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[PMID]:26235575
[Au] Autor:Ueda K; Hosokawa M; Iwakawa S
[Ad] Endereço:Department of Pharmaceutics, Kobe Pharmaceutical University.
[Ti] Título:Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells.
[So] Source:Biol Pharm Bull;38(8):1113-9, 2015.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:DNA hypermethylation, an epigenetic change that silences gene expression without altering nucleotide sequences, plays a critical role in the formation and progression of colorectal cancers as well as in the acquisition of drug resistance. Decitabine (DAC), a DNA methyltransferase 1 inhibitor of nucleoside analogues, has been shown to restore gene expression silenced by hypermethylation. In the present study, the mechanisms underlying both uridine and DAC uptake were examined in the human colon cancer cell line HCT116. Real-time polymerase chain reaction analysis revealed that ENT1 mRNA was the most abundant among the nucleoside transporters examined in HCT116 cells. The ENT1 protein was detected in the membrane fraction, as determined by Western blotting. The uptake of uridine or DAC was time- and concentration-dependent, but also Na(+)-independent. The uptake of these agents was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENTs), and was also decreased in cells treated with ENT1 small interfering RNA. The uptake of both uridine and DAC was inhibited by uridine, cytidine, adenosine, or inosine, while that of DAC was also inhibited by thymidine. The expression of MAGEA1 mRNA, the DNA of which was methylated in HCT116 cells, was increased by DAC treatment, and this increment was attenuated by concomitant treatment with NBMPR. The IC50 value of DAC was also increased in the presence of NBMPR. These results suggest that DAC is mainly taken up by ENT1 and that this uptake is one of the key determinants of the activity of DAC in HCT116 cells.
[Mh] Termos MeSH primário: Azacitidina/análogos & derivados
Neoplasias Colorretais/metabolismo
Transportador Equilibrativo 1 de Nucleosídeo/metabolismo
[Mh] Termos MeSH secundário: Antimetabólitos Antineoplásicos/metabolismo
Antimetabólitos Antineoplásicos/uso terapêutico
Azacitidina/metabolismo
Azacitidina/farmacologia
Azacitidina/uso terapêutico
Proteínas de Transporte/metabolismo
Neoplasias Colorretais/tratamento farmacológico
Metilação de DNA
Expressão Gênica/efeitos dos fármacos
Células HCT116
Seres Humanos
Antígenos Específicos de Melanoma/metabolismo
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Tioinosina/análogos & derivados
Tioinosina/farmacologia
Uridina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Carrier Proteins); 0 (Equilibrative Nucleoside Transporter 1); 0 (MAGEA1 protein, human); 0 (Melanoma-Specific Antigens); 0 (RNA, Messenger); 46S541971T (Thioinosine); 776B62CQ27 (decitabine); GV1L2DZM2Z (4-nitrobenzylthioinosine); M801H13NRU (Azacitidine); WHI7HQ7H85 (Uridine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150804
[St] Status:MEDLINE
[do] DOI:10.1248/bpb.b14-00622


  8 / 760 MEDLINE  
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[PMID]:26037416
[Au] Autor:Shimada T; Nakanishi T; Tajima H; Yamazaki M; Yokono R; Takabayashi M; Shimada T; Sawamoto K; Miyamoto K; Kitagawa H; Ohta T; Tamai I; Sai Y
[Ad] Endereço:Department of Hospital Pharmacy, University Hospital, Kanazawa University, Takara-machi, Kanazawa, 920-8641, Japan.
[Ti] Título:Saturable Hepatic Extraction of Gemcitabine Involves Biphasic Uptake Mediated by Nucleoside Transporters Equilibrative Nucleoside Transporter 1 and 2.
[So] Source:J Pharm Sci;104(9):3162-9, 2015 Sep.
[Is] ISSN:1520-6017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) is expected to be more effective and safer method to treat hepatic metastasis of pancreatic cancer compared with intravenous administration, because it affords higher tumor exposure with lower systemic exposure. Thus, a key issue for dose selection is the saturability of hepatic uptake of GEM. Therefore, we investigated GEM uptake in rat and human isolated hepatocytes. Hepatic GEM uptake involved high- and low-affinity saturable components with Km values of micromolar and millimolar order, respectively. The uptake was inhibited concentration dependently by S-(4-nitrobenzyl)-6-thioinosine (NBMPR) and was sodium-ion-independent, suggesting a contribution of equilibrative nucleoside transporters (ENTs). The concentration dependence of uptake in the presence of 0.1 µM NBMPR showed a single low-affinity binding site. Therefore, the high- and low-affinity sites correspond to ENT1 and ENT2, respectively. Our results indicate hepatic extraction of GEM is predominantly mediated by the low-affinity site (hENT2), and at clinically relevant hepatic concentrations of GEM, hENT2-mediated uptake would not be completely saturated. This is critical for HAI, because saturation of hepatic uptake would result in a marked increase of GEM concentration in the peripheral circulation, abrogating the advantage of HAI over intravenous administration in terms of severe adverse events.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Desoxicitidina/análogos & derivados
Artéria Hepática/metabolismo
Hepatócitos/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/efeitos dos fármacos
Transporte Biológico/efeitos dos fármacos
Membrana Celular/metabolismo
Desoxicitidina/administração & dosagem
Desoxicitidina/metabolismo
Transportador Equilibrativo 2 de Nucleosídeo/metabolismo
Feminino
Artéria Hepática/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Seres Humanos
Bombas de Infusão
Masculino
Proteínas de Membrana/metabolismo
Meia-Idade
Ratos
Ratos Wistar
Tioinosina/análogos & derivados
Tioinosina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (ENT1 protein, rat); 0 (Equilibrative-Nucleoside Transporter 2); 0 (Membrane Proteins); 0W860991D6 (Deoxycytidine); 46S541971T (Thioinosine); B76N6SBZ8R (gemcitabine); GV1L2DZM2Z (4-nitrobenzylthioinosine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150604
[St] Status:MEDLINE
[do] DOI:10.1002/jps.24498


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[PMID]:25853923
[Au] Autor:Kreijne JE; Seinen ML; Wilhelm AJ; Bouma G; Mulder CJ; van Bodegraven AA; de Boer NK
[Ad] Endereço:Departments of *Gastroenterology and Hepatology, and †Pharmacy, VU University Medical Center, Amsterdam; and ‡Department of Internal Medicine, Geriatrics, and Gastroenterology, Atrium-ORBIS Medical Center, Heerlen-Sittard-Geleen, the Netherlands.
[Ti] Título:Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.
[So] Source:Ther Drug Monit;37(6):797-804, 2015 Dec.
[Is] ISSN:1536-3694
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy. METHODS: Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy. RESULTS: Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01). CONCLUSIONS: This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.
[Mh] Termos MeSH primário: Azatioprina/metabolismo
Colite Ulcerativa/tratamento farmacológico
Doença de Crohn/tratamento farmacológico
Mercaptopurina/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Azatioprina/efeitos adversos
Azatioprina/uso terapêutico
Estudos de Coortes
Feminino
Seguimentos
Nucleotídeos de Guanina/metabolismo
Seres Humanos
Imunossupressores/efeitos adversos
Imunossupressores/metabolismo
Imunossupressores/uso terapêutico
Masculino
Mercaptopurina/efeitos adversos
Mercaptopurina/uso terapêutico
Meia-Idade
Estudos Retrospectivos
Fatores de Risco
Tioinosina/análogos & derivados
Tioinosina/metabolismo
Tionucleotídeos/metabolismo
Falha de Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanine Nucleotides); 0 (Immunosuppressive Agents); 0 (Thionucleotides); 15867-02-4 (6-thioguanylic acid); 46S541971T (Thioinosine); 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate); E7WED276I5 (Mercaptopurine); MRK240IY2L (Azathioprine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150409
[St] Status:MEDLINE
[do] DOI:10.1097/FTD.0000000000000213


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[PMID]:25560904
[Au] Autor:Siebel AM; Menezes FP; Capiotti KM; Kist LW; da Costa Schaefer I; Frantz JZ; Bogo MR; Da Silva RS; Bonan CD
[Ad] Endereço:1 Laboratório de Neuroquímica e Psicofarmacologia, Departamento de Biologia Celular e Molecular, Programa de Pós-Graduação em Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul , Porto Alegre, Brazil .
[Ti] Título:Role of adenosine signaling on pentylenetetrazole-induced seizures in zebrafish.
[So] Source:Zebrafish;12(2):127-36, 2015 Apr.
[Is] ISSN:1557-8542
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenosine is a well-known endogenous modulator of neuronal excitability with anticonvulsant properties. Thus, the modulation exerted by adenosine might be an effective tool to control seizures. In this study, we investigated the effects of drugs that are able to modulate adenosinergic signaling on pentylenetetrazole (PTZ)-induced seizures in adult zebrafish. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreased the latency to the onset of the tonic-clonic seizure stage. The adenosine A1 receptor agonist cyclopentyladenosine (CPA) increased the latency to reach the tonic-clonic seizure stage. Both the adenosine A2A receptor agonist and antagonist, CGS 21680 and ZM 241385, respectively, did not promote changes in seizure parameters. Pretreatment with the ecto-5'nucleotidase inhibitor adenosine 5'-(α,ß-methylene) diphosphate (AMPCP) decreased the latency to the onset of the tonic-clonic seizure stage. However, when pretreated with the adenosine deaminase (ADA) inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), or with the nucleoside transporter (NT) inhibitors, dipyridamole and S-(4-Nitrobenzyl)-6-thioinosine (NBTI), animals showed longer latency to reach the tonic-clonic seizure status. Finally, our molecular analysis of the c-fos gene expression corroborates these behavioral results. Our findings indicate that the activation of adenosine A1 receptors is an important mechanism to control the development of seizures in zebrafish. Furthermore, the actions of ecto-5'-nucleotidase, ADA, and NTs are directly involved in the control of extracellular adenosine levels and have an important role in the development of seizure episodes in zebrafish.
[Mh] Termos MeSH primário: Adenosina/metabolismo
Pentilenotetrazol/toxicidade
Convulsões/induzido quimicamente
Transdução de Sinais/efeitos dos fármacos
Peixe-Zebra
[Mh] Termos MeSH secundário: Adenina/análogos & derivados
Adenina/farmacologia
Adenosina/análogos & derivados
Adenosina/farmacologia
Antagonistas do Receptor A1 de Adenosina/farmacologia
Difosfato de Adenosina/análogos & derivados
Difosfato de Adenosina/farmacologia
Animais
Compostos de Benzil/farmacologia
Convulsivantes/toxicidade
Dipiridamol/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Genes fos/genética
Genes fos/fisiologia
Fenetilaminas/farmacologia
Inibidores de Fosfodiesterase/farmacologia
Convulsões/metabolismo
Tioinosina/análogos & derivados
Tioinosina/farmacologia
Xantinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adenosine A1 Receptor Antagonists); 0 (Benzyl Compounds); 0 (Convulsants); 0 (Phenethylamines); 0 (Phosphodiesterase Inhibitors); 0 (Xanthines); 0 (erythro-(3-nonyl-p-aminobenzyl-adenine)); 0T2A5439OE (adenosine 5'-methylenediphosphate); 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine); 46S541971T (Thioinosine); 61D2G4IYVH (Adenosine Diphosphate); 64ALC7F90C (Dipyridamole); 9PTP4FOI9E (1,3-dipropyl-8-cyclopentylxanthine); GV1L2DZM2Z (4-nitrobenzylthioinosine); JAC85A2161 (Adenine); K72T3FS567 (Adenosine); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150107
[St] Status:MEDLINE
[do] DOI:10.1089/zeb.2014.1004



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