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NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine
Affiliation:1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand;2. Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Thailand;3. Department of Pediatrics, Khon Kaen Hospital, Khon Kaen, Thailand;4. Department of Pediatrics, Udon Thani Hospital, Udon Thani, Thailand;5. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan;6. Department of Pediatrics, Faculty of Medicine, Shimane University, Izumo, Japan;1. Chemist. of Funct. Mol., Grad. Sch. Biomed. Sci., Nagasaki Univ, Japan;2. PRESTO, JST, Japan;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;4. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki, 210-9501, Japan;3. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan;4. Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan;1. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan;2. Department of Pharmacy, Kobe University Hospital, Chuo-ku, Kobe, 650-0017, Japan;3. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;4. Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;5. Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;6. Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;1. Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan;2. Laboratory of Pharmaceutics, Department of Biomedical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan;3. Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, Japan;4. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;5. Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
Abstract:6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT1513 and NUDT1512 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT1513 and NUDT1512, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.
Keywords:6-Mercaptopurine (6-MP)  Hematotoxicity  Genetic polymorphisms  Thiopurine methyltransferase (TPMT)  Nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15)  Inosine triphosphatase (ITPA)  ATP Binding cassette subfamily C Member 4 (ABCC4)  Acute lymphoblastic leukemia (ALL)  Thai
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