PMID- 18021342
OWN - NLM
STAT- MEDLINE
DCOM- 20080129
LR  - 20171116
IS  - 0269-4727 (Print)
IS  - 0269-4727 (Linking)
VI  - 32
IP  - 6
DP  - 2007 Dec
TI  - Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment 
      in children with acute lymphoblastic leukaemia?
PG  - 633-9
AB  - BACKGROUND AND OBJECTIVE: The activity of thiopurine S-methyltransferase (TPMT), 
      a key enzyme in the metabolism of purine analogues, displays wide inter-subject 
      variability partly due to a genetic polymorphism. Previous studies have suggested 
      adjusting purine analogues dosing according to TPMT activity but measurements are 
      costly and time-consuming. It is still unclear, especially under treatment, 
      whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim 
      was to study the possible correlation of TPMT genotype with phenotype. METHODS: 
      We determined the genotypic status and TMPT activity, at diagnosis and after 6 
      months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia 
      (ALL). RESULTS AND DISCUSSION: Eighty-nine per cent of the children had a 
      homozygous wild-type genotype (group 1), 11% had one or two mutant allele(s) 
      (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) 
      was significantly higher in group 1 than in group 2 (P < 0.001) but inter-group 
      levels overlapped considerably. There was considerable heterogeneity in the 
      percentage increase in TPMT activity after therapy, and little correlation 
      between metabolites ratio [6-methylmercaptopurine derivative/6-thioguanine 
      nucleotides (6-TGN)] and TPMT activity at the end of 6 months' maintenance 
      treatment. These results show that TPMT activity cannot be used as an accurate 
      tool for 6-mercaptopurine monitoring. CONCLUSION: Genotyping at diagnosis 
      identifies patients with a homozygous mutant TPMT and may prevent severe and 
      life-threatening toxicity. ALL treatment monitoring should preferentially be 
      based on repeated determinations of intracellular active metabolites (6-TGN) and 
      methylated metabolites.
FAU - Fakhoury, M
AU  - Fakhoury M
AD  - Paediatric Pharmacology and Pharmacogenetic Department, Robert Debre Hospital, 
      Paris, France.
FAU - Andreu-Gallien, J
AU  - Andreu-Gallien J
FAU - Mahr, A
AU  - Mahr A
FAU - Medard, Y
AU  - Medard Y
FAU - Azougagh, S
AU  - Azougagh S
FAU - Vilmer, E
AU  - Vilmer E
FAU - Jacqz-Aigrain, E
AU  - Jacqz-Aigrain E
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Clin Pharm Ther
JT  - Journal of clinical pharmacy and therapeutics
JID - 8704308
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
SB  - IM
MH  - Adolescent
MH  - Antimetabolites, Antineoplastic/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Erythrocytes/enzymology
MH  - Female
MH  - Genotype
MH  - Humans
MH  - Infant
MH  - Male
MH  - Mercaptopurine/metabolism/*therapeutic use
MH  - Methyltransferases/*genetics/metabolism
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/genetics
EDAT- 2007/11/21 09:00
MHDA- 2008/01/30 09:00
CRDT- 2007/11/21 09:00
PHST- 2007/11/21 09:00 [pubmed]
PHST- 2008/01/30 09:00 [medline]
PHST- 2007/11/21 09:00 [entrez]
AID - JCP858 [pii]
AID - 10.1111/j.1365-2710.2007.00858.x [doi]
PST - ppublish
SO  - J Clin Pharm Ther. 2007 Dec;32(6):633-9. doi: 10.1111/j.1365-2710.2007.00858.x.