PLoS ONE (Jan 2021)

DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes.

  • Hee Young Ju,
  • Ji Won Lee,
  • Hee Won Cho,
  • Ju Kyung Hyun,
  • Youngeun Ma,
  • Eun Sang Yi,
  • Keon Hee Yoo,
  • Ki Woong Sung,
  • Rihwa Choi,
  • Hong Hoe Koo,
  • Soo-Youn Lee

DOI
https://doi.org/10.1371/journal.pone.0245667
Journal volume & issue
Vol. 16, no. 1
p. e0245667

Abstract

Read online

BackgroundLarge inter-individual variations in drug metabolism pose a challenge in determining 6-mercaptopurine (6MP) doses. As the last product of 6MP metabolism, DNA-thioguanine nucleotide (DNA-TGN) could reflect the efficacy of 6MP, especially in patients harboring variants in the 6MP metabolism pathway. The aim of this study was to investigate the clinical significance of DNA-TGN monitoring in Korean pediatric acute lymphoblastic leukemia (ALL) patients, focusing on the NUDT15 genotype.MethodsThe subjects of this study were patients who underwent ALL treatment with 6MP. Tests for the NUDT15 and TPMT genotypes were performed, and prospective DNA-TGN and erythrocyte TGN samples were collected after two weeks or more of 6MP treatment. DNA-TGN was quantified using the liquid chromatography-tandem mass spectrometry method.ResultsA total of 471 DNA-TGN measurements in 71 patients were analyzed, which ranged from 1.0 to 903.1 fmol thioguanine/μg DNA. The 6MP intensity demonstrated a significant relationship with DNA-TGN concentration (PConclusionsPatients harboring NUDT15 variants demonstrated similar DNA-TGN concentrations even at low doses of 6MP and showed high variability in DNA-TGN. Particularly in patients with NUDT15 variants who need a reduced 6MP dose, DNA-TGN could be applied as a useful marker to monitor the therapeutic effect of 6MP.