Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia.
Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMTdeficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.
McLeod
H L
HL
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, UK.
Krynetski
E Y
EY
Relling
M V
MV
Evans
W E
WE
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics*; D001208:Asia; D044383:Black People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004739:England; D005006:Ethnicity / Q000235:genetics; D005602:France; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D007194:India; D007223:Infant; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics*; D008780:Methyltransferases / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D017354:Point Mutation; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012306:Risk; D012449:Safety; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D003062:Codon; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase