Tanaka Yoichi, Ono Rintaro, Ashiarai Miho, Sakurai Ayako, Watanabe Atsushi, Tsuchimochi Taichiro, Hosoya Yosuke, Hanajiri Ruri, Inukai Takeshi, Hasegawa Daisuke
Division of Medicinal Safety Science, National Institute of Health Sciences, Kanagawa, Japan.
Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
Cancer Chemother Pharmacol. 2025 Apr 1;95(1):50. doi: 10.1007/s00280-025-04774-9.
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).
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.
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).
NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.
本研究旨在评估Nudix水解酶15（NUDT15）变体对硫嘌呤代谢物、DNA掺入的硫鸟嘌呤核苷酸（DNA-TG）、红细胞硫鸟嘌呤核苷酸（Ery-TGNs）和甲基巯基嘌呤核苷酸（Ery-MMPN）水平的影响，以及日本急性淋巴细胞白血病（ALL）患儿中这6-巯基嘌呤（6-MP）代谢物水平之间的关联。
使用液相色谱-串联质谱法，在20例日本儿童ALL患者（171个采样点）连续临床就诊时测量DNA-TG、Ery-TGNs和Ery-MMPN水平。使用桑格测序法对NUDT15进行基因分型。
鉴定出3例NUDT15中间代谢者（IM，*1/2或1/*3）和2例慢代谢者（PM，*3/*3）。PM组的DNA-TG/剂量显著高于正常代谢者（NM）。DNA-TG水平的患者内变异系数（CV）在NUDT15基因型中相似，而IM和PM组的患者间CV高于NM组。IM和PM组的DNA-TG/Ery-TGNs比值高于NM组（p<0.01）。DNA-TG/剂量和DNA-TG/Ery-TGNs比值的范围在NUDT15表型内无差异。在NUDT15 NM中，Ery-TGNs/剂量高的患者DNA-TG/剂量也高。绝对淋巴细胞计数与DNA-TG、Ery-TGNs和Ery-MMPN水平显著相关（p<0.001）。白细胞计数与Ery-TGNs水平显著相关（p<0.02），天冬氨酸和丙氨酸转氨酶水平与Ery-MMPN水平显著相关（p<0.001）。
NUDT15表型是日本ALL儿童硫嘌呤可试用性的一个重要因素。Ery-TGNs水平可能与个体反应差异有关。
