9
views
0
recommends
+1 Recommend
1 collections
    0
    shares

      Call for Papers: Beyond Biology: The Crucial Role of Sex and Gender in Oncology

      Submit here before May 31, 2024

      About Oncology Research and Treatment: 2.4 Impact Factor I 3.3 CiteScore I 0.495 Scimago Journal & Country Rank (SJR)

      • Record: found
      • Abstract: found
      • Article: found

      Augmenting Clinical Interpretability of Thiopurine Methyltransferase Laboratory Evaluation

      research-article

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective: Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported. Patients and Methods: The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method. Results: Thirty-three patients (12.4%) were heterozygous (26 were TPMT*1/*3A, 5 TPMT*1/*2, 2 TPMT *1/*3C) and 1 was a compound heterozygote (*2/*3A). Normal and low normal TPMT activities substantially overlapped in wild-type and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient. Conclusion: Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism.

          Related collections

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

          Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease.

            Azathioprine therapy is discontinued in one-third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side-effects. To evaluate the importance of TPMT activity in the management of azathioprine therapy in inflammatory bowel disease. Clinical response, adverse effects and haematological parameters were determined and correlated with TPMT enzyme activity and genotype in 106 patients with inflammatory bowel disease. Ninety-six patients had high TPMT activity, and 10 had intermediate activity. Nineteen patients (18%) were intolerant to azathioprine. Fifteen (16%) of those with high TPMT activity were intolerant, compared with five (50%) with intermediate activity [odds ratio (OR), 5.4; 95% confidence interval (CI), 1.5-19.8]. Complete remission was achieved in 63% of cases, and complete or partial remission in 79%. Interestingly, very high TPMT activity (> 14 units/mL red blood cells) was significantly associated with non-response, irrespective of the time on azathioprine (OR, 0.21; 95% CI, 0.07-0.68). TPMT gene mutations correlated with TPMT activity. Inflammatory bowel disease patients with intermediate TPMT activity have an increased risk of azathioprine toxicity. Conversely, very high TPMT activity predicts treatment failure. TPMT genotype predicted TPMT phenotype in this study.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy.

              6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity. In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
                Bookmark

                Author and article information

                Journal
                OCL
                Oncology
                10.1159/issn.0030-2414
                Oncology
                S. Karger AG
                0030-2414
                1423-0232
                2014
                May 2014
                12 March 2014
                : 86
                : 3
                : 152-158
                Affiliations
                aDepartment of Pharmacology, Masaryk University School of Medicine, bDepartment of Laboratory Medicine and cRegional Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, dDepartment of Pediatric Oncology, University Hospital Brno, and eDepartment of Laboratory Methods, Masaryk University School of Medicine, Brno, and fDepartment of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic; gBone Marrow Transplantation Unit, Department of Pediatric Hematology and Oncology, Children's University Hospital, hInstitute of Pathological Physiology, Comenius University School of Medicine, iDepartment of Molecular Biology, Comenius University, Faculty of Natural Sciences, and jDepartment of Laboratory Medicine, Children's University Hospital, Bratislava, Slovakia
                Author notes
                *Dalibor Valik, MD, PhD, Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Zluty kopec 7, CZ-656 53 Brno (Czech Republic), E-Mail valik@mou.cz
                Article
                357407 Oncology 2014;86:152-158
                10.1159/000357407
                24643197
                d8b35cb0-291e-4825-b386-51c3ff6973a5
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 02 August 2013
                : 08 November 2013
                Page count
                Figures: 2, Pages: 7
                Categories
                Clinical Translational Research

                Oncology & Radiotherapy,Pathology,Surgery,Obstetrics & Gynecology,Pharmacology & Pharmaceutical medicine,Hematology
                Genotype-phenotype correlation,Acute lymphoblastic leukemia,Thiopurine methyltransferase,Rate-blanked pharmacophenotyping,Compound heterozygote

                Comments

                Comment on this article