Evidence map›Paper›PMID 40169418›Full record

ArticleCancer chemotherapy and pharmacology2025

The evaluation of the impact of NUDT15 variants on thiopurine metabolism in Japanese children with acute lymphoblastic leukemia.

Yoichi Tanaka, Rintaro Ono, Miho Ashiarai, Ayako Sakurai, Atsushi Watanabe, Taichiro Tsuchimochi, Yosuke Hosoya, Ruri Hanajiri, Takeshi Inukai, Daisuke Hasegawa

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Article in Cancer chemotherapy and pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

10 authors.

Yoichi TanakaDivision of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan. tanakayoichi@nihs.go.jp.ORCID http://orcid.org/0000-0002-8949-1293
Rintaro OnoDepartment of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
Miho AshiaraiDepartment of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
Ayako SakuraiDepartment of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan.
Atsushi WatanabeDepartment of Pediatrics, University of Yamanashi, Yamanashi, Japan.
Taichiro TsuchimochiDepartment of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan.
Yosuke HosoyaDepartment of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
Ruri HanajiriDivision of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan.
Takeshi InukaiDepartment of Pediatrics, University of Yamanashi, Yamanashi, Japan.
Daisuke HasegawaDepartment of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.

Funding

JSPS KAKENHI JP18K06756
6 · The paper itself

Abstract

purposeThis 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).

methodsDNA-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.

resultsThree 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).

conclusionNUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.

Indexed as

Antimetabolites, AntineoplasticMercaptopurinePrecursor Cell Lymphoblastic Leukemia-LymphomaPyrophosphatasesAdolescentChildChild, PreschoolEast Asian PeopleFemaleGenotypeGuanine NucleotidesHumansInfantJapanMaleNudix HydrolasesAntimetabolites, AntineoplasticGuanine NucleotidesMercaptopurineNudix HydrolasesNUDT15 protein, humanPyrophosphatases6-MercaptopurineChildhood acute lymphoblastic leukemiaDNA-incorporated thioguanine nucleotidesNUDT15Thioguaine nucleotidesToxicities

Identifiers

PMID40169418

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