Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring
Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity l...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.941182/full |
| _version_ | 1811203820463587328 |
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| author | Hong-Li Guo Yue-Tao Zhao Yue-Tao Zhao Wei-Jun Wang Wei-Jun Wang Na Dong Na Dong Ya-Hui Hu Yuan-Yuan Zhang Feng Chen Li Zhou Tao Li |
| author_facet | Hong-Li Guo Yue-Tao Zhao Yue-Tao Zhao Wei-Jun Wang Wei-Jun Wang Na Dong Na Dong Ya-Hui Hu Yuan-Yuan Zhang Feng Chen Li Zhou Tao Li |
| author_sort | Hong-Li Guo |
| collection | DOAJ |
| description | Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients. |
| first_indexed | 2024-04-12T03:01:25Z |
| format | Article |
| id | doaj.art-1dcbc5cf501a49b1a421d1546ac7e6a4 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T03:01:25Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-1dcbc5cf501a49b1a421d1546ac7e6a42022-12-22T03:50:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.941182941182Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoringHong-Li Guo0Yue-Tao Zhao1Yue-Tao Zhao2Wei-Jun Wang3Wei-Jun Wang4Na Dong5Na Dong6Ya-Hui Hu7Yuan-Yuan Zhang8Feng Chen9Li Zhou10Tao Li11Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, ChinaVisiting Graduate Student from School of Basic Medicine and Clinical Pharmacy, Pharmaceutical University, Nanjing, ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, ChinaVisiting Graduate Student from School of Basic Medicine and Clinical Pharmacy, Pharmaceutical University, Nanjing, ChinaInstitute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, ChinaSchool of Institute of Pharmaceutical Science, Pharmaceutical University, Nanjing, ChinaPharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaPharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaPharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaHematology and Oncology Department, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Solid Oncology, Children’s Hospital of Nanjing Medical University, Nanjing, ChinaThiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.https://www.frontiersin.org/articles/10.3389/fphar.2022.941182/fullthiopurinesmyelosuppressionpharmacogenetics“MINT” sequencing strategytherapeutic “DNA-TG” monitoring |
| spellingShingle | Hong-Li Guo Yue-Tao Zhao Yue-Tao Zhao Wei-Jun Wang Wei-Jun Wang Na Dong Na Dong Ya-Hui Hu Yuan-Yuan Zhang Feng Chen Li Zhou Tao Li Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring Frontiers in Pharmacology thiopurines myelosuppression pharmacogenetics “MINT” sequencing strategy therapeutic “DNA-TG” monitoring |
| title | Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring |
| title_full | Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring |
| title_fullStr | Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring |
| title_full_unstemmed | Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring |
| title_short | Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring |
| title_sort | optimizing thiopurine therapy in children with acute lymphoblastic leukemia a promising mint sequencing strategy and therapeutic dna tg monitoring |
| topic | thiopurines myelosuppression pharmacogenetics “MINT” sequencing strategy therapeutic “DNA-TG” monitoring |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.941182/full |
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