Quantification of Thioguanine in DNA Using Liquid Chromatography-Tandem Mass Spectrometry for Routine Thiopurine Drug Monitoring in Patients With Pediatric Acute Lymphoblastic Leukemia
- Authors
- Choi, Rihwa; Chun, Mi Ryung; Park, Jisook; Lee, Ji Won; Ju, Hee Young; Cho, Hee Won; Hyun, Ju Kyung; Koo, Hong Hoe; Yi, Eun Sang; Lee, Soo-Youn
- Issue Date
- Mar-2021
- Publisher
- 대한진단검사의학회
- Keywords
- DNA-incorporated 6-thioguanine; Liquid chromatography-tandem mass spectrometry; Therapeutic drug monitoring; Thiopurine; TPMT; NUDT15
- Citation
- Annals of Laboratory Medicine, v.41, no.2, pp 145 - 154
- Pages
- 10
- Indexed
- SCIE
SCOPUS
KCI
- Journal Title
- Annals of Laboratory Medicine
- Volume
- 41
- Number
- 2
- Start Page
- 145
- End Page
- 154
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/49188
- DOI
- 10.3343/alm.2021.41.2.145
- ISSN
- 2234-3806
2234-3814
- Abstract
- Background: We developed an assay to measure DNA-incorporated 6-thioguanine (DNA-TG) and validated its clinical applicability in Korean pediatric patients with acute lymphoblastic leukemia (ALL) in order to improve individualized thiopurine treatment and reduce the life-threatening cytotoxicity.
Methods: The DNA-TG assay was developed based on liquid chromatography-tandem mass spectrometry, with isotope-labeled TG-d3 and guanine-d3 as internal standards. This method was applied to 257 samples of pediatric ALL patients. The DNA-TG level was compared with erythrocyte TG nucleotide (RBC-TGN) level in relation to the TPMT and NUDT15 genotypes, which affect thiopurine metabolism, using Spearman's rank test and repeated measure ANOVA.
Results: For DNA-TG quantification, a linearity range of 10.0-5,000.0 fmol TG/mu g DNA; bias for accuracy of -10.4% -3.5%; coefficient of variation for intra- and inter-day precision of 3.4% and 5.8% at 80 fmol TG/mu g DNA and of 4.9% and 5.3% at 800 fmol TG/mu g DNA, respectively; and recovery of 85.7%-116.2% were achieved without matrix effects or carry-over. The median DNA-TG level in the 257 samples was 106.0 fmol TG/mu g DNA (interquartile range, 75.8-150.9). There was a strong correlation between DNA-TG and RBC-TGN levels (rho=0.68, P<0.0001). The DNA-TG/RBC-TGN ratio was significantly higher in NUDT15 intermediate metabolizers (*1/*2 and *1/*3) than in patients with wild-type alleles (P<0.0001).
Conclusions: This simple and sensitive method for measuring DNA-TG level can improve therapeutic drug monitoring for thiopurine treatment.
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Collections - 2. Clinical Science > Department of Pediatrics > 1. Journal Articles
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