Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia.
The activity of thiopurine methyltransferase (TPMT) exhibits genetic polymorphism, with approximately 1 in 300 individuals inheriting TPMT deficiency as an autosomal recessive trait, and about 11% having intermediate activity (ie, heterozygotes). Patients with TPMT deficiency accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and develop severe toxicity when treated with standard dosages of mercaptopurine. High TPMT activity has been associated with lower concentrations of TGNs, yielding a higher risk of treatment failure in children with acute lymphoblastic leukemia (ALL). As the biochemical basis of these pharmacodynamic relationships has not been fully elucidated, we investigated the variability and relationship of TPMT activity in erythrocytes and lymphoblasts from children with ALL. A 58-fold range of erythrocyte TPMT activity was found among 119 patients receiving ALL chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low intrapatient variability (coefficient of variation, 13.5%) was observed over 1 year. A 27-fold range in TPMT activity was observed in leukemic blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x 10(9) cells). TPMT activity in leukemic blasts at diagnosis was significantly correlated with TPMT in erythrocytes before therapy (rs = .75, P < .0001, N = 13). These data document extensive interpatient variability of TPMT activity in ALL blasts and establish its linkage to polymorphic TPMT activity in erythrocytes, providing a new mechanism by which erythrocytes serve as prognostic markers of mercaptopurine metabolism and TPMT activity in children with ALL.
McLeod
H L
HL
Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Relling
M V
MV
Liu
Q
Q
Pui
C H
CH
Evans
W E
WE
D000293:Adolescent; D000782:Aneuploidy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001853:Bone Marrow / Q000201:enzymology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008727:Methotrexate / Q000008:administration & dosage; D008780:Methyltransferases / Q000032:analysis*; D009363:Neoplasm Proteins / Q000032:analysis*; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011379:Prognosis; D012074:Remission Induction; D013713:Teniposide / Q000008:administration & dosage; D017211:Treatment Failure
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D003561:Cytarabine; D013713:Teniposide; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate