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https://www.readbyqxmd.com/read/28659275/novel-variants-in-nudt15-and-thiopurine-intolerance-in-children-with-acute-lymphoblastic-leukemia-from-diverse-ancestry
#1
Takaya Moriyama, Yung-Li Yang, Rina Nishii, Hany Ariffin, Chengcheng Liu, Ting-Nien Lin, Wenjian Yang, Dong-Tsamn Lin, Chih-Hsiang Yu, Shirley Kham, Ching-Hon Pui, William E Evans, Sima Jeha, Mary V Relling, Allen Eng-Juh Yeoh, Jun J Yang
Prolonged exposure to thiopurines (e.g., mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL) but is also associated with frequent dose-limiting hematopoietic toxicities, partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (e.g., TPMT). Recently, our group and others identified germline genetic variants in NUDT15 as another major cause of thiopurine-related myelosuppression, particularly in Asians and Hispanics. Herein we described three novel NUDT15 coding variants (p...
June 28, 2017: Blood
https://www.readbyqxmd.com/read/28650902/itpa-activity-in-adults-and-children-treated-with-or-without-azathioprine-relationship-between-tpmt-activity-thiopurine-metabolites-and-co-medications
#2
Boulieu Roselyne, Antony Citterio-Quentin, Mustapha Moulsma, Marie-Paule Gustin
BACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data is available on its role on thiopurine metabolites. ITPA' ability to modify the thiopurine metabolite levels currently used to optimize azathioprine (AZA) therapy in relation to TPMT activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites...
June 22, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28627831/whole-blood-thiopurine-s-methyltransferase-genotype-and-phenotype-concordance-in-iranian-kurdish-ulcerative-colitis-uc-patients
#3
Fariborz Bahrehmand, Asad Vaisi-Raygani, Amir Kiani, Homayoun Bashiri, Mahdi Zobeiri, Maryam Tanhapour, Tayebeh Pourmotabbed
BACKGROUND: Thiopurine methyl transferase (TPMT), a drug-metabolizing enzyme, catalyzes methylation and consequently, the metabolism of thiopurine compounds used for treatment of inflammatory bowel disease (IBD). Individuals who are homozygous recessive or have extremely low TPMT activity need to avoid thiopurines because of concern for significant leukopenia. The aim of this research was to determine TPMT phenotypes and genotypes in IBD patients to predict the risk of thiopurine toxicity before treatment...
May 1, 2017: Clinical Laboratory
https://www.readbyqxmd.com/read/28623449/differential-effects-of-thiopurine-methyltransferase-tpmt-and-multidrug-resistance-associated-protein-gene-4-mrp4-on-mercaptopurine-toxicity
#4
Chengcheng Liu, Laura J Janke, Jun J Yang, William E Evans, John D Schuetz, Mary V Relling
PURPOSE: Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear. METHODS: We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously...
June 16, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28566182/nudt15-p-r139c-variant-is-common-and-strongly-associated-with-azathioprine-induced-early-leukopenia-and-severe-alopecia-in-korean-patients-with-various-neurological-diseases
#5
Sun-Young Kim, Jin-Hong Shin, Jin-Sung Park, Sa-Yoon Kang, Tai-Seung Nam, Jong Kuk Kim, Ki-Jong Park, So-Young Huh, Ji Seon Oh, Boram Kang, Dae-Seong Kim
Azathioprine (AZA)-induced leukopenia is a relatively common complication in Korean patients. In addition to variation in TPMT (thiopurine S-methyltransferase), the NUDT15 p.R139C variant was recently identified to have a strong association with AZA-induced leukopenia. We investigated these associations in Korean patients undergoing AZA treatment with various neurological diseases. Among 84 enrolled patients, 20 (23.8%; 7 early, 13 late) exhibited leukopenia. The NUDT15 p.R139C variant was associated with leukopenia (OR: 11...
July 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28552060/thiopurine-s-methyltransferase-as-a-pharmacogenetic-biomarker-significance-of-testing-and-review-of-major-methods
#6
Chingiz Asadov, Gunay Aliyeva, Kamala Mustafayeva
Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at the high risk of severe adverse drug reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity...
May 28, 2017: Cardiovascular & Hematological Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28525791/determination-of-thiopurine-s-methyltransferase-activity-by-hydrophilic-interaction-liquid-chromatography-hyphenated-with-mass-spectrometry
#7
Daniel Pecher, Svetlana Dokupilová, Zuzana Zelinková, Maikel Peppelenbosch, Veronika Mikušová, Peter Mikuš
Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines used in the therapy of inflammatory bowel diseases (IBD). In this work a new progressive method for the determination of TPMT activity in red blood cells lysates was developed. Analysis was carried out by means of hydrophilic interaction liquid chromatography (HILIC) hyphenated with mass spectrometry (MS). In comparison with reversed-phase high-performance liquid chromatography (RP-HPLC), that has been typically applied in determination of TPMT activity, the HILIC significantly improved the analytical signal provided by MS, shortened analysis time, and improved chromatographic resolution...
May 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28507448/thiopurine-s-methyltransferase-polymorphisms-in-acute-lymphoblastic-leukemia-inflammatory-bowel-disease-and-autoimmune-disorders-influence-on-treatment-response
#8
REVIEW
Rachid Abaji, Maja Krajinovic
The thiopurine S-methyltransferase (TPMT) gene encodes for the TPMT enzyme that plays a crucial role in the metabolism of thiopurine drugs. Genetic polymorphisms in this gene can affect the activity of the TPMT enzyme and have been correlated with variability in response to treatment with thiopurines. Advances in the pharmacogenetics of TPMT allowed the development of dosing recommendations and treatment strategies to optimize and individualize prescribing thiopurine in an attempt to enhance treatment efficacy while minimizing toxicity...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28500740/children-with-low-risk-acute-lymphoblastic-leukemia-are-at-highest-risk-of-second-cancers
#9
Stine N Nielsen, Frank Eriksson, Susanne Rosthoej, Mette K Andersen, Erik Forestier, Henrik Hasle, Lisa L Hjalgrim, Ann Aasberg, Jonas Abrahamsson, Mats Heyman, Ólafur G Jónsson, Kaie Pruunsild, Goda E Vaitkeviciené, Kim Vettenranta, Kjeld Schmiegelow
BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]...
May 13, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28498350/comparison-of-direct-sequencing-real-time-pcr-high-resolution-melt-pcr-hrm-and-pcr-restriction-fragment-length-polymorphism-pcr-rflp-analysis-for-genotyping-of-common-thiopurine-intolerant-variant-alleles-nudt15-c-415c-t-and-tpmt-c-719a-g-tpmt-3c
#10
Wai-Ying Fong, Chi-Chun Ho, Wing-Tat Poon
Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard...
May 12, 2017: Diagnostics
https://www.readbyqxmd.com/read/28476189/analysis-of-thiopurine-s-methyltransferase-deficient-alleles-in-acute-lymphoblastic-leukemia-patients-in-mexican-patients
#11
Silvia Jiménez-Morales, Mireya Ramírez-Florencio, Juan Manuel Mejía-Aranguré, Juan Carlos Núñez-Enríquez, Carolina Bekker-Mendez, José Luis Torres-Escalante, Janet Flores-Lujano, Elva Jiménez-Hernández, María Del Carmen Rodríguez-Zepeda, Yelda A Leal, Pablo Miguel González-Montalvo, Francisco Pantoja-Guillen, José Gabriel Peñaloza-Gonzalez, Erick Israel Gutiérrez-Juárez, Nora Nancy Núñez-Villegas, Maria Luisa Pérez-Saldivar, Francisco Xavier Guerra-Castillo, Luz Victoria Flores-Villegas, María Teresa Ramos-Cervantes, José Manuel Fragoso, María Guadalupe García-Escalante, Doris Del Carmen Pinto-Escalante, Julián Ramírez-Bello, Alfredo Hidalgo-Miranda
BACKGROUND AND AIMS: It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase (TPMT) mutant allele carriers are at high risk to develop severe and potentially fatal hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico...
November 2016: Archives of Medical Research
https://www.readbyqxmd.com/read/28462921/one-amino-acid-makes-a-difference-characterization-of-a-new-tpmt-allele-and-the-influence-of-sam-on-tpmt-stability
#12
Yan Ping Heidi Iu, Sara Helander, Anna Zimdahl Kahlin, Chun Wah Cheng, Chi Chung Shek, Moon Ho Leung, Björn Wallner, Lars-Göran Mårtensson, Malin Lindqvist Appell
Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A > C, named TPMT*41, together with the more common variant *3C c.719A > G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively...
May 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28445188/tpmt-comt-and-acyp2-genetic-variants-in-paediatric-cancer-patients-with-cisplatin-induced-ototoxicity
#13
Signe Thiesen, Peng Yin, Andrea L Jorgensen, Jieying Eunice Zhang, Valentina Manzo, Laurence McEvoy, Christopher Barton, Susan Picton, Simon Bailey, Penelope Brock, Harish Vyas, David Walker, Guy Makin, Srinivas Bandi, Barry Pizer, Daniel B Hawcutt, Munir Pirmohamed
OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design...
June 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28406961/pharmacogenetic-variants-in-tpmt-alter-cellular-responses-to-cisplatin-in-inner-ear-cell-lines
#14
Amit P Bhavsar, Erandika P Gunaretnam, Yuling Li, Jafar S Hasbullah, Bruce C Carleton, Colin J D Ross
Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant...
2017: PloS One
https://www.readbyqxmd.com/read/28391009/the-promise-of-pharmacogenomics-in-reducing-toxicity-during-acute-lymphoblastic-leukemia-maintenance-treatment
#15
REVIEW
Shoshana Rudin, Marcus Marable, R Stephanie Huang
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity...
April 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/28346068/institutional-profile-university-of-florida-health-personalized-medicine-program
#16
Larisa H Cavallari, Kristin W Weitzel, Amanda R Elsey, Xinyue Liu, Scott A Mosley, Donald M Smith, Benjamin J Staley, Almut G Winterstein, Carol A Mathews, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo, Petr Starostik, Michael J Clare-Salzler, David R Nelson, Julie A Johnson
The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations...
April 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28321040/whole-exome-sequencing-detects-variants-of-genes-that-mediate-response-to-anticancer-drugs
#17
Sumiko Ohnami, Takeshi Nagashima, Kenichi Urakami, Yuji Shimoda, Fukumi Kamada, Junko Saito, Akane Naruoka, Masakuni Serizawa, Yoko Masuda, Shumpei Ohnami, Masatoshi Kusuhara, Ken Yamaguchi
Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023)...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28317081/pharmacogenetic-predictors-of-treatment-related-toxicity-among-children-with-acute-lymphoblastic-leukemia
#18
REVIEW
Rochelle R Maxwell, Peter D Cole
PURPOSE OF REVIEW: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). RECENT FINDINGS: Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities...
March 20, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28295989/pharmacokinetics-of-two-6-mercaptopurine-liquid-formulations-in-children-with-acute-lymphoblastic-leukemia
#19
Jaszianne A Tolbert, Shasha Bai, Susan M Abdel-Rahman, Keith J August, Scott J Weir, Gregory L Kearns, Kathleen A Neville
BACKGROUND: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. METHODS: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts...
March 10, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28277331/nudt15-genotype-distributions-in-the-korean-population
#20
Hyoung-Tae Kim, Rihwa Choi, Hong-Hee Won, Yon Ho Choe, Ben Kang, Kiwuk Lee, Hong Hoe Koo, Keon Hee Yoo, Young-Ho Kim, Soo-Youn Lee
Thiopurines have a narrow therapeutic range because of frequent toxicity (i.e. marrow suppression), which is only partly explained by TPMT genetic polymorphisms, especially within Asian populations. Recent studies have identified NUDT15 variation as another important factor affecting thiopurine metabolism. In this study, a total of four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal) were genotyped in 920 Korean individuals using direct sequencing of NUDT15 for the first time in a Korean population...
May 2017: Pharmacogenetics and Genomics
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