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Thiopurine metabolites

Nicholas C K Valerie, Anna Hagenkort, Brent D G Page, Geoffrey Masuyer, Daniel Rehling, Megan Carter, Luka Bevc, Patrick Herr, Evert Homan, Nina G Sheppard, Pål Stenmark, Ann-Sofie Jemth, Thomas Helleday
Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics, their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention on the basis of its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C, and thiopurine sensitivity...
September 15, 2016: Cancer Research
Maria Giulia Battelli, Letizia Polito, Massimo Bortolotti Andrea Bolognesi
The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs...
July 24, 2016: Current Medicinal Chemistry
Kjeld Schmiegelow, Jacob Nersting, Stine Nygaard Nielsen, Mats Heyman, Finn Wesenberg, Jon Kristinsson, Kim Vettenranta, Henrik Schrøeder, Richard Weinshilboum, Katrine Lykke Jensen, Kathrine Grell, Susanne Rosthoej
BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1...
July 22, 2016: Pediatric Blood & Cancer
Dennis R Wong, Marieke J H Coenen, Sita H Vermeulen, Luc J J Derijks, Corine J van Marrewijk, Olaf H Klungel, Hans Scheffer, Barbara Franke, Henk-Jan Guchelaar, Dirk J de Jong, Leopold G J B Engels, André L M Verbeek, Piet M Hooymans
BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in IBD patients is related to TPMT deficiency. We determined the predictive value of 6-thioguanine nucleotide (6TGN) and 6-methylmercaptopurine ribonucleotide (6MMPR) concentrations one week after initiation (T1) for development of leukopenia during the first eight weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomised controlled TOPIC trial (ClinicalTrials...
July 9, 2016: Journal of Crohn's & Colitis
Cristina Martínez Faci, Ignacio Ros Arnal, José M Martínez de Zabarte Fernández, Jordi Sorribes Estorch, Mónica López Campos, Carmen Rodríguez-Vigil Iturrate
Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts...
August 1, 2016: Archivos Argentinos de Pediatría
Sally A Coulthard, Phil Berry, Sarah McGarrity, Azhar Ansari, Christopher P F Redfern
Adverse reactions and non-response are common in patients treated with thiopurine drugs. Current monitoring of drug metabolite levels for guiding treatment are limited to analysis of thioguanine nucleotides (TGNs) in erythrocytes after chemical derivatisation. Erythrocytes are not the target tissue and TGN levels show poor correlations with clinical response. We have developed a sensitive assay to quantify deoxythioguanosine (dTG) without derivatisation in the DNA of nucleated blood cells. Using liquid chromatography and detection by tandem mass spectrometry, an intra- and inter-assay variability below 7...
August 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Agata Ladić, Nada Božina, Vladimir Borzan, Marko Brinar, Boris Vucelić, Silvija Cuković-Cavka
Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reaction-based assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers...
March 2016: Acta Clinica Croatica
Polychronis Pavlidis, Panagiotis Stamoulos, Answar Abdulrehman, Patrick Kerr, Claire Bull, John Duley, Azhar Ansari
BACKGROUND: Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling...
July 2016: Inflammatory Bowel Diseases
Romein W G Dujardin, Berrie Meijer, Nanne K H de Boer, Geert R D'Haens, Mark Löwenberg
BACKGROUND: Thiopurines are commonly used drugs in inflammatory bowel disease. Intracellular levels of thiopurine metabolites [i.e. 6-thioguaninenucleotides (6-TGN)] are associated with efficacy and toxicity. Because 6-TGN measurement is not globally available, the mean corpuscular volume (MCV) has been proposed as a surrogate marker for monitoring thiopurine therapy. AIMS: To analyze the relationship between MCV and efficacy of thiopurines, defined as either response to therapy or 6-TGN levels...
September 2016: European Journal of Gastroenterology & Hepatology
Imke Atreya, Alexandra Diall, Radovan Dvorsky, Raja Atreya, Christian Henninger, Mathias Grün, Ute Hofmann, Elke Schaeffeler, Rocío López-Posadas, Ilse Daehn, Stefanie Zenker, Michael Döbrönti, Clemens Neufert, Ulrike Billmeier, Sebastian Zundler, Gerhard Fritz, Matthias Schwab, Markus F Neurath
BACKGROUND AND AIMS: The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. METHODS: Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients...
October 2016: Journal of Crohn's & Colitis
Zhang Fangbin, Gao Xiang, Ding Liang, Liu Hui, Wang Xueding, Chen Baili, Bi Huichang, Xiao Yinglian, Cheng Peng, Zhao Lizi, Chu Yanjun, Xu Feng, Chen Minhu, Huang Min, Hu Pinjin
Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420  pmol/8 × 10(8) RBC (odds ratio [OR] = 7...
April 2016: Medicine (Baltimore)
Xavier Roblin, Nicolas Williet, Laurent Peyrin-Biroulet
6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i...
June 2016: Inflammatory Bowel Diseases
Takaya Moriyama, Rina Nishii, Virginia Perez-Andreu, Wenjian Yang, Federico Antillon Klussmann, Xujie Zhao, Ting-Nien Lin, Keito Hoshitsuki, Jacob Nersting, Kentaro Kihira, Ute Hofmann, Yoshihiro Komada, Motohiro Kato, Robert McCorkle, Lie Li, Katsuyoshi Koh, Cesar Rolando Najera, Shirley Kow-Yin Kham, Tomoya Isobe, Zhiwei Chen, Edwynn Kean-Hui Chiew, Deepa Bhojwani, Cynthia Jeffries, Yan Lu, Matthias Schwab, Hiroto Inaba, Ching-Hon Pui, Mary V Relling, Atsushi Manabe, Hiroki Hori, Kjeld Schmiegelow, Allen E J Yeoh, William E Evans, Jun J Yang
Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p...
April 2016: Nature Genetics
W Moon, E V Loftus
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...
February 14, 2016: Alimentary Pharmacology & Therapeutics
Rimma Goldberg, Gregory Moore, Georgina Cunningham, Julien Schulberg, Philip Marsh, Steven Brown, William Connell, Mark Lust, Michael A Kamm, Sally Bell
BACKGROUND: Thiopurine use in inflammatory bowel disease (IBD) is limited by drug toxicity and lack of therapeutic efficacy. We assessed the utility of thiopurine metabolite testing and the relationship between disease activity, dose, and metabolite levels in a real world setting. METHODS: Patients identified from pathology databases (2007-2012) at two tertiary IBD centers were included if they had thiopurines for at least four weeks. Demographics, dose, test indication, clinical status, action taken, and outcome were obtained by retrospective medical record review...
March 2016: Journal of Gastroenterology and Hepatology
Ryan A McConnell, Uma Mahadevan
Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active...
January 2016: Inflammatory Bowel Diseases
N M Heerasing, J F Ng, D Dowling
BACKGROUND: The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV...
April 2016: Internal Medicine Journal
Oren Bernheim, Jordan Axelrad, Steven H Itzkowitz, Jean-Frederic Colombel
Immunomodulators and biologic agents are effective in treating inflammatory bowel diseases (IBDs), and recent evidence supports their introduction earlier in the disease course. An important concern to both patients and physicians considering immunosuppression (IS) for the treatment of IBD is the potential associated cancer risk. Several important clinical questions deserve attention with respect to IBD therapy and cancer. First, does medical therapy for IBD predispose to developing cancer? Second, in an IBD patient with a history of cancer, does IBD therapy impact cancer recurrence? Third, once cancer develops in an IBD patient, is the cancer outcome different? Finally, in an IBD patient with current cancer, does the cancer therapy affect IBD outcomes? In a recent multicentric study, patients were identified based on a diagnosis of IBD and cancer with subsequent exposure to anti-tumor necrosis factor α (anti-TNFα arm), thiopurines or methotrexate (antimetabolite arm) or without subsequent IS exposure (control arm)...
September 14, 2015: Digestive Diseases
Amit Assa, Irit Avni, Ofer Ben-Bassat, Yaron Niv, Raanan Shamir
BACKGROUND: Different practice guidelines and consensus statements for both pediatric- and adult-onset inflammatory bowel disease exist. Although variations in medical care among gastroenterologists are common, it is unknown whether there are fundamental differences between disciplines. The primary aim of the present study was to investigate differences in common practices across disciplines. METHODS: This was a prospective, questionnaire-based survey of gastroenterologists attending gastroenterology meetings in Israel...
March 2016: Journal of Pediatric Gastroenterology and Nutrition
Mehmet Coskun, Casper Steenholdt, Nanne K de Boer, Ole Haagen Nielsen
Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety...
March 2016: Clinical Pharmacokinetics
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