Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity.
OBJECTIVE
The response to 6-mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6-thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype.


METHODS
Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children.


RESULTS
TPMT activities at diagnosis ranged from 5.5 to 18.5 units ml(-1) packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75 mg m(-2) ranged from 187 to 594 pmol 6TGNs, median 327, and 0.5 to 22.0 nmol MeMPs, median 4.5, per 8 x 10(8) RBCs. TPMT activity was not significantly related to the generation of MeMPs (r(s) = 0.06), but was negatively correlated to 6TGNs (r(s) = -0.44, P<0.025, n=29). TGNs were related to neutropenia at the point of dose reduction (r(s) = -0.5, P<0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal (r(s)= -0.41, P<0.05).


CONCLUSIONS
These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.
Lennard
L
L
University of Sheffield, Department of Medicine and Pharmacology, Royal Hallamshire Hospital, U.K.
Welch
J C
JC
Lilleyman
J S
JS
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004912:Erythrocytes / Q000201:enzymology; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D008727:Methotrexate / Q000008:administration & dosage; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D013866:Thioguanine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D014750:Vincristine / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide; D003907:Dexamethasone; D003520:Cyclophosphamide; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D008727:Methotrexate