PMID- 1973780
OWN - NLM
STAT- MEDLINE
DCOM- 19900827
LR  - 20220318
IS  - 0140-6736 (Print)
IS  - 0140-6736 (Linking)
VI  - 336
IP  - 8709
DP  - 1990 Jul 28
TI  - Genetic variation in response to 6-mercaptopurine for childhood acute 
      lymphoblastic leukaemia.
PG  - 225-9
AB  - 6-mercaptopurine (6-MP) can be inactivated by S-methylation, which is catalysed 
      by thiopurine methyltransferase (TPMT). An alternative metabolic route leads to 
      the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). To investigate 
      whether these two pathways compete with each other to affect the therapeutic 
      response to 6-MP, 6-TGN concentrations and TPMT enzymatic activity were measured 
      in erythrocytes (RBC) from 95 children on long-term 6-MP therapy for 
      lymphoblastic leukaemia (ALL). RBC TPMT activities were also measured in 130 
      control children and 104 long-term survivors of ALL no longer on treatment. The 
      95 children on 6-MP showed wide interindividual differences in RBC 6-TGN 
      concentrations at the full protocol dose of 75 mg/m2, and RBC 6-TGN 
      concentrations correlated negatively with RBC TPMT activity. Children with 6-TGN 
      concentrations below the group median had higher TPMT activities and a higher 
      subsequent relapse rate. 50 of the 104 long-term survivors had been treated with 
      "gentle" low-dose protocols, and this subgroup contained an excess of children 
      with lower TPMT activities compared with normal controls. These results indicate 
      that genetically determined TPMT activity may be a substantial regulator of the 
      cytotoxic effect of 6-MP, an effect which in turn could be important in 
      influencing the outcome of therapy for childhood ALL.
FAU - Lennard, L
AU  - Lennard L
AD  - University of Sheffield, Department of Medicine and Pharmacology, UK.
FAU - Lilleyman, J S
AU  - Lilleyman JS
FAU - Van Loon, J
AU  - Van Loon J
FAU - Weinshilboum, R M
AU  - Weinshilboum RM
LA  - eng
GR  - ES 55110/ES/NIEHS NIH HHS/United States
GR  - GM 28157/GM/NIGMS NIH HHS/United States
GR  - GM 35720/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
SB  - IM
MH  - Actuarial Analysis
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Analysis of Variance
MH  - Child
MH  - Child, Preschool
MH  - Drug Administration Schedule
MH  - Drug Evaluation
MH  - Erythrocytes/enzymology
MH  - Female
MH  - Follow-Up Studies
MH  - Guanine Nucleotides/*blood/genetics/metabolism
MH  - Homozygote
MH  - Humans
MH  - Male
MH  - Mercaptopurine/administration & dosage/metabolism/*therapeutic use
MH  - Methyltransferases/*blood/genetics
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood/drug therapy/*enzymology
MH  - Prognosis
MH  - Remission Induction/methods
MH  - Thionucleotides/*blood/genetics/metabolism
MH  - Time Factors
EDAT- 1990/07/28 00:00
MHDA- 1990/07/28 00:01
CRDT- 1990/07/28 00:00
PHST- 1990/07/28 00:00 [pubmed]
PHST- 1990/07/28 00:01 [medline]
PHST- 1990/07/28 00:00 [entrez]
AID - 0140-6736(90)91745-V [pii]
AID - 10.1016/0140-6736(90)91745-v [doi]
PST - ppublish
SO  - Lancet. 1990 Jul 28;336(8709):225-9. doi: 10.1016/0140-6736(90)91745-v.