METHODSFifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before and 66 hours after start of high-dose MTX infusions. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukemic cell line. RESULTSForty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity compared to genotype at the time of diagnosis. TPMT decreased significantly 66 hours after the start of high-dose MTX infusions (-9.2 per cent, p=0.013). MTX bound to recombinant TPMT protein and inhibited the TPMT enzyme to a remaining activity of 16 percent. CONCLUSIONSThis study shows that TPMT genotyping should be preferred in children with ALL, since 40per cent of TPMT wild-type children are at risk of initial under-dosing of 6-MP in cases where 3 only TPMT enzyme activity is determined. MTX inhibits the TPMT enzyme activity after high-dose MTX infusions due to protein binding.

The thiopurines (6-mercaptopurine [6-MP], 6-thioguanine and azathioprine) are cytotoxic drugs used in the treatment of acute lymphoblastic leukemia (ALL), inflammatory bowel diseases, certain autoimmune diseases and after transplantation. The metabolism of

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