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https://www.readbyqxmd.com/read/28903549/nudt15-variants-cause-hematopoietic-toxicity-with-low-6-tgn-levels-in-children-with-acute-lymphoblastic-leukemia
#1
Eun Sang Yi, Young Bae Choi, Rihwa Choi, Na Hee Lee, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Soo-Youn Lee, Hong Hoe Koo
Purpose: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Materials and Methods: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant)...
September 13, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/28883280/susceptibility-to-6-mercaptopurine-toxicity-related-with-nudt15-and-abcc4-variants-in-japanese-childhood-acute-lymphoblastic-leukemia
#2
Yoichi Tanaka
6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28877179/adherence-to-6-mercaptopurine-in-children-and-adolescents-with-acute-lymphoblastic-leukemia
#3
Mervat Alsous, Rana Abu Farha, Eman Alefishat, Suha Al Omar, Deema Momani, Alia Gharabli, James McElnay, Robert Horne, Rawad Rihani
OBJECTIVE: Studies on children with Acute Lymphoblastic Leukemia (ALL) reported non-adherence in 2-54% of cases. The primary objective of this study was to assess rates of adherence to 6-MP using two different methods in children and adolescents with ALL. Secondary aim was to identify factors that influence adherence to 6-MP in children with ALL. METHODS: All eligible children with ALL who are (≤ 19) years old and receive 6-MP therapy for at least 1 month were approached to participate in the study...
2017: PloS One
https://www.readbyqxmd.com/read/28844800/paternal-use-of-azathioprine-6-mercaptopurine-or-methotrexate-within-3-months-before-conception-and-long-term-health-outcomes-in-the-offspring-a-nationwide-cohort-study
#4
S Friedman, M D Larsen, B Magnussen, L R Jølving, P de Silva, B M Nørgård
PURPOSE: We examined the effect of preconception paternal use of azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate (MTX) and the risk of adverse long-term outcomes in the offspring. METHODS: This study included all children born in Denmark from 1 January 1997 through 2013. Exposed cohort: children fathered by men who used AZA/6-MP (N=735) or MTX (N=209) within three months before conception; unexposed cohort: children fathered by men who did not use AZA/6-MP/MTX (N=1,056,524)...
August 24, 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/28835099/glutathione-sensitive-hyaluronic-acid-mercaptopurine-prodrug-linked-via-carbonyl-vinyl-sulfide-a-robust-and-cd44-targeted-nanomedicine-for-leukemia
#5
Jie Qiu, Ru Cheng, Jian Zhang, Huanli Sun, Chao Deng, Fenghua Meng, Zhiyuan Zhong
6-Mercaptopurine (6-MP) is an essential medicine used for treating leukemia in the clinics. 6-MP suffers, however, from poor water solubility, low bioavailability, and significant side effects. Here, we designed CD44-targeted glutathione-sensitive hyaluronic acid-mercaptopurine prodrug (HA-GS-MP) linked via carbonyl vinyl sulfide for safer and enhanced treatment of acute myeloid leukemia (AML). HA-GS-MP obtained with 50 kDa HA and 6-MP conjugation content of 6.9 wt % showed excellent water solubility with a hydrodynamic size of ca...
September 1, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28818801/development-and-validation-of-a-reliable-method-for-thiopurine-methyltransferase-tpmt-enzyme-activity-in-human-whole-blood-by-lc-ms-ms-an-application-for-phenotypic-and-genotypic-correlations
#6
Supaporn Wiwattanakul, Santirhat Prommas, Nuttawut Jenjirattithigarn, Siwalee Santon, Apichaya Puangpetch, Samart Pakakasama, Usanarat Anurathapan, Chonlaphat Sukasem
A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of thiopurine methyltransferase (TPMT) activity in human whole blood lysate, based on conversion of 6-mercaptopurine (6-MP) by TPMT to 6-methylmercaptopurine (6-MMP) using S-adenosyl-l-methionine (SAM) as the methyl donor. This method was improved from the previous laborious method for washing of red cell lysate preparation to develop whole blood EDTA lysate. In addition, the TPMT incubation was optimized and the chromatography was performed in a short runtime of 7min on a C18-column by detection via triple quadrupole mass spectrometry...
October 25, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28710878/6-mercaptopurine-modifies-cerebrospinal-fluid-t-cell-abnormalities-in-paediatric-opsoclonus-myoclonus-as-steroid-sparer
#7
M R Pranzatelli, E D Tate, T J Allison
The purpose of this study was to evaluate the capacity of 6-mercaptopurine (6-MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus-myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion) using a comprehensive panel of cell surface adhesion, activation and maturation markers by flow cytometry, and referenced to 18 paediatric controls. Drug metabolites, lymphocyte counts and liver function tests were used clinically to monitoring therapeutic range and toxicity...
July 15, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28681659/the-relationship-of-genetics-nursing-practice-and-informatics-tools-in-6-mercaptopurine-dosing-in-pediatric-oncology-formula-see-text
#8
Wendy J Haylett
An antileukemic agent prescribed for pediatric oncology patients during the maintenance phase of therapy for acute lymphoblastic leukemia, 6-mercaptopurine (6-MP), is highly influenced by genetic variations in the thiopurine S-methyltransferase enzyme. As such, 6-MP must be dosed so that patients with 1 or 2 inactive thiopurine S-methyltransferase alleles will not incur an increased risk for myelosuppression or other toxicities. Informatics tools such as clinical decision support systems are useful for the application of this and similar pharmacogenetics information to the realm of nursing and clinical practice for safe and effective patient care...
September 2017: Journal of Pediatric Oncology Nursing: Official Journal of the Association of Pediatric Oncology Nurses
https://www.readbyqxmd.com/read/28574837/6-mercaptopurine-promotes-energetic-failure-in-proliferating-t-cells
#9
Ana A Fernández-Ramos, Catherine Marchetti-Laurent, Virginie Poindessous, Samantha Antonio, Pierre Laurent-Puig, Sylvie Bortoli, Marie-Anne Loriot, Nicolas Pallet
The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1α (HIF-1α). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28554266/tolerability-profile-of-thiopurines-in-inflammatory-bowel-disease-a-prospective-experience
#10
Fabio Salvatore Macaluso, Sara Renna, Marcello Maida, Mariangela Dimarco, Chiara Sapienza, Marco Affronti, Emanuele Orlando, Giulia Rizzuto, Rosalba Orlando, Marco Ventimiglia, Mario Cottone, Ambrogio Orlando
OBJECTIVES: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. MATERIALS AND METHODS: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported...
September 2017: Scandinavian Journal of Gastroenterology
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/28436311/role-of-6-mercaptopurine-in-the-potential-therapeutic-targets-dna-base-pairs-and-g-quadruplex-dna-insights-from-quantum-chemical-and-molecular-dynamics-simulations
#12
R Radhika, R Shankar, S Vijayakumar, P Kolandaivel
The theoretical studies on DNA with the anticancer drug 6-Mercaptopurine (6-MP) are investigated using theoretical methods to shed light on drug designing. Among the DNA base pairs considered, 6-MP is stacked with GC with the highest interaction energy of -46.19 kcal/mol. Structural parameters revealed that structure of the DNA base pairs is deviated from the planarity of the equilibrium position due to the formation of hydrogen bonds and stacking interactions with 6-MP. These deviations are verified through the systematic comparison between X-H bond contraction and elongation and the associated blue shift and red shift values by both NBO analysis and vibrational analysis...
May 24, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28424090/targeted-endomyocardial-biopsy-guided-by-real-time-cardiovascular-magnetic-resonance
#13
Christina Unterberg-Buchwald, Christian Oliver Ritter, Verena Reupke, Robin Niklas Wilke, Christine Stadelmann, Michael Steinmetz, Andreas Schuster, Gerd Hasenfuß, Joachim Lotz, Martin Uecker
BACKGROUND: Endomyocardial biopsies (EMB) are an important diagnostic tool for myocarditis and other infiltrative cardiac diseases. Routinely, biopsies are obtained under fluoroscopic guidance with a substantial radiation burden. Despite procedural success, there is a large sampling error caused by missing the affected myocardium. Therefore, multiple (>6) biopsies are taken in the clinical setting. In cardiovascular magnetic resonance (CMR), late gadolinium enhancement (LGE) depicts areas of affected myocardium in myocarditis or in other infiltrative cardiomyopathies...
April 19, 2017: Journal of Cardiovascular Magnetic Resonance
https://www.readbyqxmd.com/read/28418010/interaction-between-nudt15-and-abcc4-variants-enhances-intolerability-of-6-mercaptopurine-in-japanese-patients-with-childhood-acute-lymphoblastic-leukemia
#14
Y Tanaka, H Nakadate, K Kondoh, K Nakamura, K Koh, A Manabe
6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0...
April 18, 2017: Pharmacogenomics Journal
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/28339328/mercaptopurine-ingestion-habits-red-cell-thioguanine-nucleotide-levels-and-relapse-risk-in-children-with-acute-lymphoblastic-leukemia-a-report-from-the-children-s-oncology-group-study-aall03n1
#16
Wendy Landier, Lindsey Hageman, Yanjun Chen, Nancy Kornegay, William E Evans, Bruce C Bostrom, Jacqueline Casillas, David S Dickens, Anne L Angiolillo, Glen Lew, Kelly W Maloney, Leo Mascarenhas, A Kim Ritchey, Amanda M Termuhlen, William L Carroll, Mary V Relling, F Lennie Wong, Smita Bhatia
Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%...
May 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28301625/successful-treatment-of-generalized-essential-telangiectasia-with-6-mercaptopurine
#17
Alex M Glazer, Bryan D Sofen, Darrell S Rigel, Jerome L Shupack
<p>Generalized essential telangiectasia (GET) is a notoriously difficult to treat disorder with no current satisfactory treatments. This case and discussion report the use of 6-mercaptopurine (6-MP) as a successful treatment for GET. Moreover, we show that GET may represent a state of increased angiogenesis, a paradigm shift from the current understanding that these telangiectasias represent dilatations of only pre-existing vessels. This new view of GET may drive others to look at novel agents for treatment...
March 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28295989/pharmacokinetics-of-two-6-mercaptopurine-liquid-formulations-in-children-with-acute-lymphoblastic-leukemia
#18
RANDOMIZED CONTROLLED TRIAL
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...
August 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28212467/comparison-of-6-mercaptopurine-with-6-thioguanine-for-the-analysis-of-thiopurine-s-methyltransferase-activity-in-human-erythrocyte-by-lc-ms-ms
#19
Shenghui Mei, Xindi Li, Xiaoqing Gong, Xiaoyi Zhang, Xingang Li, Li Yang, Leting Zhu, Heng Zhou, Yonghong Liu, Anna Zhou, Xinghu Zhang, Zhigang Zhao
Thiopurines (TPDs) are first-line drugs in treating neuromyelitis optica spectrum disorders (NMOSD). Evaluation of thiopurine S-methyltransferase activity (TPMT), a major determinant of TPD toxicity, before TPD treatment using 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrate was suggested. However, the equivalent of the two substrates in TPMT activity evaluation was unknown, and an alternative substrate was required in TPMT activity evaluation in patients who were already taking 6-MP or 6-TG. Before evaluating the agreement of 6-MP and 6-TG in TPMT activity measurement in patients with NMOSD, the affinity of the two substrates for the active center of TPMT should be established...
September 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28205273/in-vitro-responses-to-known-in-vivo-genotoxic-agents-in-mouse-germ-cells
#20
Khaled Habas, Martin H Brinkworth, Diana Anderson
Genotoxic compounds have induced DNA damage in male germ cells and have been associated with adverse clinical outcomes including enhanced risks for maternal, paternal and offspring health. DNA strand breaks represent a great threat to the genomic integrity of germ cells. Such integrity is essential to maintain spermatogenesis and prevent reproduction failure. The Comet assay results revealed that the incubation of isolated germ cells with n-ethyl-n-nitrosourea (ENU), 6-mercaptopurine (6-MP) and methyl methanesulphonate (MMS) led to increase in length of Olive tail moment and % tail DNA when compared with the untreated control cells and these effects were concentration-dependent...
March 2017: Environmental and Molecular Mutagenesis
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