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

L. Lennard, J. S. Lilleyman, J. Van Loon, Richard M Weinshilboum

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)225-229
Number of pages5
JournalThe Lancet
Volume336
Issue number8709
DOIs
StatePublished - Jul 28 1990

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thiopurine methyltransferase
6-Mercaptopurine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Survivors
Therapeutics
Methylation
Erythrocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. / Lennard, L.; Lilleyman, J. S.; Van Loon, J.; Weinshilboum, Richard M.

In: The Lancet, Vol. 336, No. 8709, 28.07.1990, p. 225-229.

Research output: Contribution to journalArticle

Lennard, L. ; Lilleyman, J. S. ; Van Loon, J. ; Weinshilboum, Richard M. / Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. In: The Lancet. 1990 ; Vol. 336, No. 8709. pp. 225-229.
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