Genetic polymorphisms of thiopurine S-methyltrans-ferase in a cohort of patients with systemic autoimmune diseases

Rheumatology Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy.
Clinical and experimental rheumatology (Impact Factor: 2.72). 03/2009; 27(2):321-4.
Source: PubMed


Azathioprine (AZA) is a purine antimetabolite, prodrug widely used as a disease modifying drug in several rheumatic conditions. The aim of the present study was to evaluate the prevalence of TPMT genetic polymorphisms in a cohort of Italian Caucasian patients affected by rheumatic diseases and treated with AZA, and to establish correlations with the tolerability of AZA treatment.
Seventy-eight Caucasian patients, 16 males and 62 females, median age 41 years (min-max: 24-76) were enrolled. At the time of evaluation, the median duration of treatment with AZA was 8 months (min-max: 2-150 months); the median dose of AZA per kg of body weight was 1.42 mg (min-max: 0.5-2). Among the 78 patients evaluated, 76 presented a wild type genotype (TPMT *1), while polymorphic alleles were identified in 2 patients (2.6%). Twenty-five patients (32%) experienced different types of adverse events (AE) under AZA treatment. Eighteen patients (23.1%) discontinued AZA because of AE. No correlation was observed between polymorphic TPMT alleles and the development of AE.
Our analysis supports the view that TPMT genotyping alone is not sufficient to adequately personalize the AZA dosage in rheumatic patients. Further studies based on phenotypic analysis of TPMT enzyme and assay of AZA metabolite appear to be required.

3 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.
    Cancer Chemotherapy and Pharmacology 03/2011; 68(5):1155-9. DOI:10.1007/s00280-011-1599-7 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The concept of prodrugs has been successfully executed for life cycle management options of several approved drugs and drugs in development. In addition to imparting ideal biopharmaceutical properties, such as solubility, permeability and lipophilicity, some prodrug concepts have also enabled site-specific drug delivery, prolonged the duration of therapeutic effect and improved therapeutic index. The strategic inclusion of prodrug concept during drug discovery and early development process brings in some unique challenges. The communication provides balanced perspectives on the rational use and challenges of prodrug concept during the drug discovery and development process.
    European Journal of Drug Metabolism and Pharmacokinetics 03/2011; 36(2):49-59. DOI:10.1007/s13318-011-0035-z · 1.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many studies focus on monitoring response to chemotherapy, adverse effects and prediction of therapeutic effects, which depend on individual gene variability. The amount of various polymorphisms in genes involved in the folate cycle, and other metabolic pathways involved in the metabolism of chemotherapeutic drugs, are an essential topic of such studies. This work focuses on the design and establishment of a pharmacogenetically relevant panel, which could be applied to the rapid genotyping of patients treated with thiopurines, 5-fluorouracil, methotrexate, irinotecan and glucocorticoids. A total of 97 variations in 36 genes associated with side effects of chemotherapeutic treatment were selected. Of these, 94 SNPs were genotyped by the arrayed primer extension (APEX; Asper Biotech Ltd) microarray method or direct sequencing. Variations of tandem repeats or gene deletions were genotyped by capillary electrophoresis and PCR detection. A total of 300 DNA samples from healthy volunteers were tested to estimate genotype frequencies for a Slovak population. All data were checked for Hardy-Weinberg equilibrium and genetic linkage between variations. We designed an APEX microarray for genotyping pharmacologically relevant polymorphisms in patients undergoing chemotherapy. We estimated genotype frequencies for all 97 polymorphisms testing 300 individuals from the Slovak population, which may also serve as an estimate of central European frequencies. These data also allowed for the testing of genetic linkage between loci. Many of the determined genotype frequencies in this study were in similar ranges found in other European populations but four SNPs, rs11760837 (p = 0.018), rs1801265 (p = 0.0375), rs1801394 (p = 0.0066) and rs182455 (p = 0.0083), demonstrated stronger deviation. Genetic variability in genes involved in metabolic pathways of chemotherapeutic drugs, such as methotrexate, 5-fluorouracil, thiopurines or irinotecan, is responsible for individual therapy response and development of side effects. A comprehensive approach in genotyping of numerous variants is aimed to improve individual access to patients and the selection of appropriate drugs for treatment. The APEX microarray method is a valuable tool for fast, reliable and cost-effective genotyping of variants which can be used for the typing of known variants in patients prior to treatment as well as in studies searching for new genotype-phenotype associations. The opportunity of adding additional variants during the study makes the APEX microarray technology flexible and suitable for such trials. Original submitted 4 October 2010; Revision submitted 23 November 2010.
    Pharmacogenomics 04/2011; 12(4):577-92. DOI:10.2217/pgs.10.199 · 3.22 Impact Factor
Show more