title: Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?
abstract: The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.
authors.affiliation: University of Sheffield Department of Medicine, Royal Hallamshire Hospital, UK.
authors.forename: L
authors.initials: L
authors.lastname: Lennard
authors.forename: H A
authors.initials: HA
authors.lastname: Davies
authors.forename: J S
authors.initials: JS
authors.lastname: Lilleyman
mesh_terms: D000293:Adolescent; D002648:Child; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009503:Neutropenia / Q000139:chemically induced; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013866:Thioguanine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors
chemical_list: D015122:Mercaptopurine; D013866:Thioguanine