Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia.
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.
Lennard
L
L
University of Sheffield, Department of Medicine and Pharmacology, UK.
Lilleyman
J S
JS
Van Loon
J
J
Weinshilboum
R M
RM
D000206:Actuarial Analysis; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005500:Follow-Up Studies; D006150:Guanine Nucleotides / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000097:blood* / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D011379:Prognosis; D012074:Remission Induction / Q000379:methods; D013873:Thionucleotides / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase