Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects.
Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme, catalysing S-methylation of aromatic and heterocyclic sulphhydryl compounds. TPMT activities and genotypes have been determined in patients with acute lymphoblastic leukaemia (ALL) and in control children. Median red blood cell (RBC) TPMT activity in ALL patients at diagnosis was significantly lower than in controls (median 11.5 pmol/10(7) RBC*hr; range 1.7-30.7; n = 191 vs. 14.6 pmol/10(7) RBC*hr; range 1.6-50.7; n = 140). This reduction of TPMT activity in ALL patients was not due to differences in the frequency of mutations in the TPMT gene. In concordance with other authors, we found a higher TPMT activity during maintenance treatment with 6-mercaptopurine (6MP) than at diagnosis and in controls. However, we observed that TPMT activity was already significantly increased after the induction therapy, before the patients received 6MP (median 17.5; range 3.9-40.3 pmol/10(7) RBC*hr; n = 139). In vitro experiments indicate that the early increase of TPMT activity during treatment may be explained by the use of antifolates, e.g., methotrexate and trimethoprim.
Brouwer
Connie
C
Department of Pediatrics, Division of Hemato-Oncology, University Medical Center, St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
De Abreu
Ronney A
RA
Keizer-Garritsen
Jenneke J
JJ
Lambooy
Lambert H J
LH
Ament
Kai
K
ter Riet
Patricia G J H
PG
van Wering
Elisabeth R
ER
Trijbels
Frans J M
FJ
Veerman
Anjo J P
AJ
Hoogerbrugge
Peter M
PM
Bökkerink
Jos P M
JP
D002648:Child; D002675:Child, Preschool; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D014295:Trimethoprim / Q000627:therapeutic use
D005493:Folic Acid Antagonists; D014295:Trimethoprim; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate