Augmenting clinical interpretability of thiopurine methyltransferase laboratory evaluation

Oncology. 2014;86(3):152-8. doi: 10.1159/000357407. Epub 2014 Mar 12.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Asparaginase / therapeutic use
  • Chromatography, High Pressure Liquid
  • Cyclophosphamide / therapeutic use
  • Cytarabine / therapeutic use
  • Czech Republic
  • Daunorubicin / therapeutic use
  • Erythrocyte Membrane / enzymology
  • Female
  • Genetic Association Studies
  • Humans
  • Inflammatory Bowel Diseases / blood
  • Male
  • Mercaptopurine / therapeutic use
  • Methotrexate / therapeutic use
  • Methyltransferases / deficiency*
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Polymerase Chain Reaction
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Prednisone / therapeutic use
  • Slovakia
  • Vincristine / therapeutic use


  • Cytarabine
  • Vincristine
  • Cyclophosphamide
  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase
  • Asparaginase
  • Prednisone
  • Methotrexate
  • Daunorubicin

Supplementary concepts

  • AIEOP acute lymphoblastic leukemia protocol