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Thiopurine Methyltransferase (thiopurine + methyltransferase)

Distribution by Scientific Domains
Medical Sciences71%

Terms modified by Thiopurine Methyltransferase

  • thiopurine methyltransferase activity
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    Selected Abstracts

    The low frequency of defective TPMT alleles in Turkish population: A study on pediatric patients with acute lymphoblastic leukemia,

    AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2007
    Tugba Boyunegmez Tumer
    6-Mercaptopurine (6MP) is an essential anticancer drug used in the treatment of childhood acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe toxicity or efficacy of 6MP. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C, are responsible over the 80% of low or undetectable enzyme activity. The frequencies of these variants were investigated among 106 children with ALL in Turkish population. TPMT*3A and TPMT*3C were the only deficiency alleles detected in Turkish population with an allele frequency of 0.9% for both. While *3C allele frequency in Turkish population was found to be very similar to Asian and other Caucasian populations, *3A allele frequency was significantly (P < 0.05) lower. So far, studies showed that the genetic polymorphisms of other drug metabolizing enzymes like CYP2E1, CYP1A1, GSTM1/ T1 in Turkish population were similar to Caucasian populations. However, we found that the distribution of TPMT polymorphisms in Turkish population was significantly lower than those in other Caucasians like British, French, and Italian whereas the distributions of TPMT variants were found to be very similar to Kazak population which is also Caucasian in ethnic origin. In this study, the clinical histories of the patients in the sample population were also examined, retrospectively. The patients with heterozygous or homozygous mutant genotypes had developed severe neutropenia and infection during 6MP therapy. The study provides the first data on the frequency of common TPMT variants in the Turkish population, based on analysis of pediatric patients with ALL. Am. J. Hematol. 82:906,910, 2007. © 2007 Wiley-Liss, Inc. [source]

    5-Aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine

    INFLAMMATORY BOWEL DISEASES, Issue 4 2006
    Scott Hande MD
    Abstract Background: Small uncontrolled trials have suggested that 5-aminosalicylate (5-ASA) medications increase 6-thioguanine nucleotide (6-TGn) levels in adults with Crohn's disease (CD) on azathioprine (AZA) or 6-mercaptopurine (6-MP), presumably through the inhibition of thiopurine methyltransferase (TPMT). We tested the theory that coadministration of 5-ASA agents with AZA/6-MP results in higher 6-TGn levels in a large cohort of children and adults with CD or ulcerative colitis (UC). Methods: A retrospective cohort study identified all children and adults treated for IBD with AZA/6-MP at 2 tertiary medical centers. Patients were included if their TPMT genotype was known and 6-TGn and 6-methymercaptopurine (6-MMP) levels had been obtained after 3 months of clinical remission at a stable dose of AZA/6-MP. 6-TGn and 6-MMP levels were compared between patients taking and those not taking 5-ASA medications through the use of linear regression models to identify and adjust for potentially confounding variables. Results: Of the 126 patients included, 88 were taking 5-ASA medications. Patients on 5-ASA agents had higher mean 6-TGn levels after adjustment for confounding variables (,6-TGn, 47.6 ± 21.8 pmol/8 × 108 red blood cells; P = 0.03). CD and TPMT heterozygosity was independently associated with higher 6-TGn levels (P = 0.01 and P = 0.03, respectively). 5-ASA exposure was not associated with a change in 6-MMP levels. Conclusions: We found that 5-ASA therapy is associated with higher 6-TGn levels in children and adults with IBD on 6-MP/AZA. TPMT inhibition may not explain this effect because 5-ASA exposure did not affect 6-MMP levels. The observed association of CD with higher 6-TGn levels is novel and needs to be verified in prospective studies. [source]

    Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010
    A. ANSARI
    Aliment Pharmacol Ther,31, 640,647 Summary Background, The thiopurine drugs, azathioprine and mercaptopurine (MP), are established treatments for IBD. However, therapeutic failure caused by adverse drug reactions occurs frequently. Aim, To study combination of allopurinol with reduced-dose thiopurine in an attempt to avoid adverse drug reactions in the treatment of IBD. Methods, Patients with drug reactions to full-dose thiopurines were recruited for combination therapy in two IBD centres in this retrospective study. Dosing was guided by measuring thiopurine methyltransferase (for UK patients) or thioguanine nucleotides and methyl-6MP (Australian patients). Response was monitored by clinical activity indices. Results, Of 41 patients, 25 had non-hepatic and 16 had hepatitic reactions. Clinical remission was achieved in 32 patients (78%) with a median follow-up of 41 weeks (range 0.5,400). Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. The relative risk of having an adverse reaction with methyl-6MP in the top interquartile range was 2.7 (1.3,28) times that with methyl-6MP in the lower three quartiles (95% confidence interval). Conclusion, The combined experience from our centres is the largest reported experience of this combination therapy strategy in IBD, and the first to provide evidence for benefit in thiopurine and allopurinol co-therapy to avoid non-hepatitic adverse drug reactions. [source]

    Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease

    ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008
    A. ANSARI
    Summary Background, Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid ,triple therapy' improved renal graft survival. Aim, To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study. Methods, Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests. Results, Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (steatosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions. Conclusions, Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses. [source]

    Human thiopurine methyltransferase activity varies with red blood cell age

    BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2001
    L. Lennard
    Aims, Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. Methods,Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age-fractionated on Percoll density gradients. Results,Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654,18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age-fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5,12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. Conclusions,Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs. [source]

    Freshwater selenium-methylating bacterial thiopurine methyltransferases: diversity and molecular phylogeny

    ENVIRONMENTAL MICROBIOLOGY, Issue 2 2005
    S. Favre-Bonté
    Summary The diversity of bacterial thiopurine methyltransferases (bTPMT) among five natural Se-methylating freshwaters was investigated by polymerase chain reaction (PCR) screenings and sequencings. DNA sequence analyses confirmed the cloned products' identity and revealed a broad diversity of freshwater TPMTs. Neighbour-joining (NJ) phylogenetic analyses combining these sequences, all GenBank entries closely related to these sequences and deduced TPMTs obtained in this work from selected ,-proteobacteria showed TPMTs to form a distinct radiation, closely related to UbiG methyltransferases. Inside the TPMT phylogenetic cluster, eukaryote sequences diverged early from the bacterial ones, and all the bacterial database entries belonged to a subgroup of ,-proteobacteria, with an apparent lateral transfer of a particular allele to ,-proteobacteria of Bordetella. The NJ phylogenetic tree revealed 22 bTPMT lineages, 10 of which harboured freshwater sequences. All lineages showed deep and long branches indicative of major genetic drifts outside regions encoding highly conserved domains. Selected residues among these highly variable domains could reflect adaptations for particular ecological niches. PCR lineage-specific primers differentiated Se-methylating freshwaters according to their ,tpm lineage' signatures. Most freshwater tpm alleles were found to be distinct from those available in the databases, but a group of tpm was found encoding TPMTs identical to an Aeromonas veronii TPMT characterized in this work. [source]