Role of TPMT and ITPA variants in mercaptopurine disposition

Role of TPMT and ITPA variants in mercaptopurine disposition Purpose To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. Methods Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rig- shospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. Results Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype LA LA patients (TPMT 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r = 0.37, p = 0.001), but plateaued at higher mEry-TGN lev- WT LA els. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT patients as compared to TPMT patients but WT LA no difference in DNA-TG indices was observed between ITPA and ITPA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (r = 0.25, p = 0.001). Conclusions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Chemotherapy and Pharmacology Springer Journals

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Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Medicine & Public Health; Oncology; Pharmacology/Toxicology; Cancer Research
ISSN
0344-5704
eISSN
1432-0843
D.O.I.
10.1007/s00280-018-3525-8
Publisher site
See Article on Publisher Site

Abstract

Purpose To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. Methods Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rig- shospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. Results Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype LA LA patients (TPMT 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r = 0.37, p = 0.001), but plateaued at higher mEry-TGN lev- WT LA els. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT patients as compared to TPMT patients but WT LA no difference in DNA-TG indices was observed between ITPA and ITPA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (r = 0.25, p = 0.001). Conclusions

Journal

Cancer Chemotherapy and PharmacologySpringer Journals

Published: Feb 1, 2018

References

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