Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia

Lancet. 1990 Jul 28;336(8709):225-9. doi: 10.1016/0140-6736(90)91745-v.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actuarial Analysis
  • Administration, Oral
  • Adolescent
  • Adult
  • Analysis of Variance
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Drug Evaluation
  • Erythrocytes / enzymology
  • Female
  • Follow-Up Studies
  • Guanine Nucleotides / blood*
  • Guanine Nucleotides / genetics
  • Guanine Nucleotides / metabolism
  • Homozygote
  • Humans
  • Male
  • Mercaptopurine / administration & dosage
  • Mercaptopurine / metabolism
  • Mercaptopurine / therapeutic use*
  • Methyltransferases / blood*
  • Methyltransferases / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
  • Prognosis
  • Remission Induction / methods
  • Thionucleotides / blood*
  • Thionucleotides / genetics
  • Thionucleotides / metabolism
  • Time Factors


  • Guanine Nucleotides
  • Thionucleotides
  • 6-thioguanylic acid
  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase