L Lennard1, T S Chew, J S Lilleyman. 1. University of Sheffield Division of Clinical Sciences, Section of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
Abstract
AIMS: Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. METHODS: Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age-fractionated on Percoll density gradients. RESULTS: Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654-18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age-fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5-12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. CONCLUSIONS: Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.
AIMS: Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. METHODS: Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age-fractionated on Percoll density gradients. RESULTS: Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654-18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age-fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5-12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. CONCLUSIONS: Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.
Authors: J H BURCHENAL; M L MURPHY; R R ELLISON; M P SYKES; T C TAN; L A LEONE; D A KARNOFSKY; L F CRAVER; H W DARGEON; C P RHOADS Journal: Blood Date: 1953-11 Impact factor: 22.113
Authors: M V Relling; M L Hancock; G K Rivera; J T Sandlund; R C Ribeiro; E Y Krynetski; C H Pui; W E Evans Journal: J Natl Cancer Inst Date: 1999-12-01 Impact factor: 13.506
Authors: R Tamm; R Mägi; R Tremmel; S Winter; E Mihailov; A Smid; A Möricke; K Klein; M Schrappe; M Stanulla; R Houlston; R Weinshilboum; Irena Mlinarič Raščan; A Metspalu; L Milani; M Schwab; E Schaeffeler Journal: Clin Pharmacol Ther Date: 2017-02-01 Impact factor: 6.875
Authors: C Liu; W Yang; D Pei; C Cheng; C Smith; W Landier; L Hageman; Y Chen; J J Yang; K R Crews; N Kornegay; S E Karol; F L Wong; S Jeha; J T Sandlund; R C Ribeiro; J E Rubnitz; M L Metzger; C-H Pui; W E Evans; S Bhatia; M V Relling Journal: Clin Pharmacol Ther Date: 2016-11-18 Impact factor: 6.875
Authors: U Hindorf; M Lindqvist; C Peterson; P Söderkvist; M Ström; H Hjortswang; A Pousette; S Almer Journal: Gut Date: 2006-03-16 Impact factor: 23.059
Authors: Kjeld Schmiegelow; Ibrahim Al-Modhwahi; Mette Klarskov Andersen; Mikael Behrendtz; Erik Forestier; Henrik Hasle; Mats Heyman; Jon Kristinsson; Jacob Nersting; Randi Nygaard; Anne Louise Svendsen; Kim Vettenranta; Richard Weinshilboum Journal: Blood Date: 2009-02-17 Impact factor: 22.113