title: Thiopurine S-methyltransferase phenotype-genotype correlation in children with acute lymphoblastic leukemia.
abstract: Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. TPMT activity exhibits an interindividual variability mainly as a result of genetic polymorphism. Patients with intermediate or deficient TPMT activity are at risk for toxicity after receiving standard doses of thiopurine drugs. The aim of this study was to determine the TPMT genotype and phenotype (activity) and investigate the correlation between TPMT genotype and enzyme activity in 43 Polish children receiving 6-MP during maintenance therapy in course of acute lymphoblastic leukemia (ALL), in 16 children with ALL at diagnosis and 39 healthy controls. TPMT activity was measured in RBC by HPLC method. Patients were genotyped for TPMT *2, *3A and *3C variant allelesusing PCR-RFLP and allele-specific PCR methods. In the group of children with ALL during maintenance therapy, median TPMT activity (29.3 nmol 6-mMP g(-1) Hb h(-1)) was significantly higher compared to the group of children with ALL at diagnosis (20.6 nmol 6-mMP g(-1) Hb h(-1), p = 0.0028), as well as to the control group (22.8 nmol 6-mMP g(-1) Hb h(-1), p = 0.0002). Percentages of individuals heterozygous for TPMT variant allele in respective groups were: 9.3, 6.2 and 15.5% (p > 0.05). In all the study groups heterozygous patients manifested a significantly lower TPMT activity as compared to the wild type homozygotes (16.7 +/- 2.1 vs. 31.2 +/- 6.8 nmol 6-mMP g(-1) Hb h(-1), p = 0.002, in children during maintenance therapy, 11.9 +/- 2.7 vs. 24.6 +/- 9.5, p = 0.0003, in the combined group of children with ALL at diagnosis and controls). The results present that commencement of the thiopurine therapy caused an increase in the TPMT activity in RBCs by approximately 20%. All patients heterozygous for the TPMT variant allele revealed decreased TPMT activity compared to TPMT wild-type patients. Since decreased TPMT activity is associated with higher risk for toxicity after receiving standard doses of thiopurine drugs, pretreatment determination of TPMT status, with phenotypic or genetic assay, should be performed routinely, also in Poland.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, University of Medical Sciences, Swiecickiego 6, 60-781 Poznań, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Chrzanowska
authors.forename: Marta
authors.initials: M
authors.lastname: Kuehn
authors.forename: Danuta
authors.initials: D
authors.lastname: Januszkiewicz-Lewandowska
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kurzawski
authors.forename: Marek
authors.initials: M
authors.lastname: Droździk
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000493:pharmacokinetics / Q000627:therapeutic use; D008780:Methyltransferases / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*
chemical_list: D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase