{"title":"The evaluation of the impact of NUDT15 variants on thiopurine metabolism in Japanese children with acute lymphoblastic leukemia.","authors":"Yoichi Tanaka, Rintaro Ono, Miho Ashiarai, Ayako Sakurai, Atsushi Watanabe, Taichiro Tsuchimochi, Yosuke Hosoya, Ruri Hanajiri, Takeshi Inukai, Daisuke Hasegawa","doi":"10.1007/s00280-025-04774-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL).</p><p><strong>Methods: </strong>DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing.</p><p><strong>Results: </strong>Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001).</p><p><strong>Conclusion: </strong>NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"50"},"PeriodicalIF":2.3000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-025-04774-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL).
Methods: DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing.
Results: Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001).
Conclusion: NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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