The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia
| Autor: | Hiroki Hori, Ting-Nien Lin, Takaya Moriyama, Atsushi Manabe, Katsuyoshi Koh, Rina Nishii, Kentaro Kihira, Motohiro Kato, Nersting Jacob, Jun J. Yang, Hiroto Inaba, Hidemi Toyoda, Kjeld Schmiegelow |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Adolescent Pharmacogenomic Variants Metabolite Antineoplastic Agents Pharmacology Polymorphism Single Nucleotide Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Germline mutation Japan Genetics medicine Humans Precision Medicine Pyrophosphatases General Pharmacology Toxicology and Pharmaceutics Child Thioguanine Molecular Biology Germ-Line Mutation Genetics (clinical) Thiopurine methyltransferase biology business.industry Infant Precursor Cell Lymphoblastic Leukemia-Lymphoma Mercaptopurine Haematopoiesis 030104 developmental biology chemistry Bone marrow suppression Purines Child Preschool 030220 oncology & carcinogenesis Toxicity biology.protein Molecular Medicine Female business medicine.drug |
| Zdroj: | Pharmacogenetics and Genomics. 27:236-239 |
| ISSN: | 1744-6872 |
| DOI: | 10.1097/fpc.0000000000000282 |
| Popis: | Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments. |
| Databáze: | OpenAIRE |
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