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1
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Jarrar Y, Ghishan M, Khirfan F, Hakooz N. Genetic variants in NUDT15 gene their clinical implications in cancer therapy. Drug Metab Pers Ther 2025:dmdi-2025-0003. [PMID: 40219790 DOI: 10.1515/dmpt-2025-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025]
Abstract
Individual variations in the response to thiopurine-based anticancer drugs are influenced by genetic and environmental factors, making it challenging to optimize dosing and minimize toxicity. Among the key genes involved, genetic variations in the nudix hydrolase 15 (NUDT15) gene affect on thiopurine metabolism, thus influencing drug efficacy and the risk of severe adverse effects, such as myelosuppression, These variations also contribute to inter-individual differences in drug tolerance and clinical outcomes. Despite the recognized impact of NUDT15 variations, there has been limited comprehensive exploration of these variants and their clinical significance in thiopurine therapy. This review provides a thorough analysis of NUDT15 genetic variants by synthesizing findings from prior clinical studies and employing in silico analyses to predict the functional effects of variants with uncertain significance. Comprehensive analysis of NUDT15 variants and their interactions with other metabolic pathways could offer valuable insights for advancing personalized medicine in cancer treatment. This review aims to establish a foundation for integrating NUDT15 genetic information into the clinical practice, reducing toxicity, and improved therapeutic outcomes in patients undergoing thiopurine-based chemotherapy.
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Affiliation(s)
- Yazun Jarrar
- Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt, Jordan
| | - Maria Ghishan
- Department of Pharmaceutical Science, College of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Fatima Khirfan
- Department of Pharmaceutical Science, College of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Nancy Hakooz
- School of Pharmacy, The University of Jordan, Amman, Jordan
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2
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Shi Y, Wei Z, Feng Y, Gan Y, Li G, Deng Y. The diagnosis and treatment of disorders of nucleic acid/nucleotide metabolism associated with epilepsy. ACTA EPILEPTOLOGICA 2025; 7:23. [PMID: 40217360 PMCID: PMC11959797 DOI: 10.1186/s42494-025-00201-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 01/06/2025] [Indexed: 04/15/2025] Open
Abstract
Epilepsy is a prevalent paroxysmal disorder in the field of neurology. Among the six etiologies of epilepsy, metabolic causes are relatively uncommon in clinical practice. Metabolic disorders encompass amino acid metabolism disorders, organic acid metabolism disorders, and other related conditions. Seizures resulting from nucleic acid/nucleotide metabolism disorders are even more infrequent. This review provides an overview of several studies on nucleic acid/nucleotide metabolism disorders associated with epilepsy, including adenosine succinate lyase deficiency, Lesch-Nyhan syndrome, and aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) deficiency, among others. The potential pathogenesis, phenotypic features, diagnostic pathways, and therapeutic approaches of these diseases are discussed in this review. The goal is to help clinicians make an accurate diagnosis when encountering rare nucleic acid/nucleotide metabolism disorders with multi-system symptoms and manifestations of epilepsy.
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Affiliation(s)
- Yuqing Shi
- Xi'an Medical University, Xi'an, 710021, People's Republic of China
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China
| | - Zihan Wei
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China
| | - Yan Feng
- Xi'an Medical University, Xi'an, 710021, People's Republic of China
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China
| | - Yajing Gan
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China
| | - Guoyan Li
- Xi'an Medical University, Xi'an, 710021, People's Republic of China
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China
| | - Yanchun Deng
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, People's Republic of China.
- Xijing Institute of Epileptic Encephalopathy, Shaanxi, Xi'an, 710065, People's Republic of China.
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3
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Salazar J, Riera P, Gordillo J, Altès A, Martínez M, Serès M, Llaó J, Giordano A, Garcia-Planella E. Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn's disease patients. THE PHARMACOGENOMICS JOURNAL 2024; 24:20. [PMID: 38906864 DOI: 10.1038/s41397-024-00341-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 06/23/2024]
Abstract
Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.
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Affiliation(s)
- Juliana Salazar
- Translational Medical Oncology Laboratory, Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Pau Riera
- Pharmacy Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
- CIBERER U-705, Barcelona, Spain
| | - Jordi Gordillo
- IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Albert Altès
- Hematology Department, Fundació Althaia, Manresa, Barcelona, Spain
| | - Miguel Martínez
- IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Montserrat Serès
- Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jordina Llaó
- IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Antonio Giordano
- IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
- Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
| | - Esther Garcia-Planella
- IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain
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4
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Burgis NE, VanWormer K, Robbins D, Smith J. An ITPA Enzyme with Improved Substrate Selectivity. Protein J 2024; 43:62-71. [PMID: 38066288 PMCID: PMC10901923 DOI: 10.1007/s10930-023-10162-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2023] [Indexed: 02/29/2024]
Abstract
Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in neural development which is not understood. Polymorphism of the ITPA gene affects outcomes for both ribavirin and thiopurine based therapies and nearly one third of the human population is thought to harbor ITPA polymorphism. In a previous site-directed mutagenesis alanine screen of the ITPA substrate selectivity pocket, we identified the ITPA mutant, E22A, as a gain-of function mutant with enhanced ITP hydrolysis activity. Here we report a rational enzyme engineering experiment to investigate the biochemical properties of position 22 ITPA mutants and find that the E22D ITPA has two- and four-fold improved substrate selectivity for ITP over the canonical purine triphosphates ATP and GTP, respectively, while maintaining biological activity. The novel E22D ITPA should be considered as a platform for further development of ITPA therapies.
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Affiliation(s)
- Nicholas E Burgis
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA.
| | - Kandise VanWormer
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
| | - Devin Robbins
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
| | - Jonathan Smith
- Department of Chemistry, Biochemistry & Physics, Eastern Washington University, Cheney, WA, 99004, USA
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5
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Omichi N, Kishita Y, Nakama M, Sasai H, Terazawa A, Kobayashi E, Fushimi T, Sugiyama Y, Ichimoto K, Nitta KR, Yatsuka Y, Ohtake A, Murayama K, Okazaki Y. Novel ITPA variants identified by whole genome sequencing and RNA sequencing. J Hum Genet 2023; 68:649-652. [PMID: 37246162 DOI: 10.1038/s10038-023-01156-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/30/2023]
Abstract
Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.
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Affiliation(s)
- Nanako Omichi
- Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
| | - Yoshihito Kishita
- Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Mina Nakama
- Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
- Clinical Genetics Center, Gifu University Hospital, Gifu, Japan
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Hideo Sasai
- Clinical Genetics Center, Gifu University Hospital, Gifu, Japan
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
- Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
| | - Atsushi Terazawa
- Department of Pediatric Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan
| | - Emiko Kobayashi
- Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan
| | - Takuya Fushimi
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Yohei Sugiyama
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Keiko Ichimoto
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Kazuhiro R Nitta
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yukiko Yatsuka
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Akira Ohtake
- Department of Pediatrics and Clinical Genomics, Saitama Medical University, Moroyama, Saitama, Japan
- Center for Intractable Diseases, Saitama Medical University Hospital, Moroyama, Saitama, Japan
| | - Kei Murayama
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
- Center for Medical Genetics, Chiba Children's Hospital, Chiba, Japan
| | - Yasushi Okazaki
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
- Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
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6
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Schroader JH, Handley MT, Reddy K. Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1790. [PMID: 37092460 DOI: 10.1002/wrna.1790] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/10/2023] [Accepted: 03/20/2023] [Indexed: 04/25/2023]
Abstract
Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA-associated pathogenesis which provides evidence for RNA dysfunction. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.
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Affiliation(s)
- Jacob H Schroader
- The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
- Department of Biological Sciences, University at Albany, State University of New York, Albany, New York, USA
| | - Mark T Handley
- Faculty of Biological Sciences, University of Leeds, Leeds, UK
| | - Kaalak Reddy
- The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
- Department of Biological Sciences, University at Albany, State University of New York, Albany, New York, USA
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7
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Heidari M, Khalili M, Balouchi F, Roozbeh J, Shamsaefar AR, Malek Hosseini SA, Karimi MH. Investigation of the Association Between ITPA Gene 94C>A Sequence Variant and Kidney Transplant Rejection in Iranian Kidney Transplant Recipients. EXP CLIN TRANSPLANT 2023; 21:652-656. [PMID: 37698399 DOI: 10.6002/ect.2023.0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
OBJECTIVES Thiopurine prodrugs are commonly used in kidney transplant recipients. Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene. Alteration of ITPA gene is one of the pharmacogenetic sequence variants possibly involved in thiopurine metabolism. The ITPA 94C>A sequence variant (C-to-A substitution at nucleotide 94) is associated with an increased risk of adverse drug reactions in patients treated with the thiopurine drug. The aim of the present study was to investigate the effect of the ITPA 94C>A gene sequence variant in kidney transplant recipients. MATERIALS AND METHODS The genotyping of the ITPA rs1127354 variant was performed by the polymerase chain reaction restriction fragment length polymorphism method in 140 kidney transplant recipients and in 100 control participants. Data were analyzed with SPSS statistical software. RESULTS The results revealed a significant difference between control and nonrejection groups regarding the rs1127354 genotype and allele frequency. No significant difference was found between the rejection and nonrejection groups regarding the rs1127354 genotype and allele frequency. Also, a significant association was observed between the ageofthe control group and age of the rejection group. No significant differences between sex and underlying disease in patients with or without rejection were observed. CONCLUSIONS We observed no significant differences between rejection and nonrejection transplant. Further studies are recommended, in a larger population and with different ethnicities.
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Affiliation(s)
- Mozhdeh Heidari
- >From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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8
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ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia. Mediterr J Hematol Infect Dis 2023; 15:e2023024. [PMID: 36908869 PMCID: PMC10000882 DOI: 10.4084/mjhid.2023.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023] Open
Abstract
Background 6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016). Conclusions HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.
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9
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Heidari M, Khalili M, Malek Hosseini SA, Geramizadeh B, Shamsaefar AR, Balouchi F, Karimi MH. Investigation of the Association Between the ITPA Gene 94C>A Gene Sequence Variant and Liver Transplant Rejection in Iranian Liver Transplant Recipients. EXP CLIN TRANSPLANT 2022; 20:1094-1098. [PMID: 36718008 DOI: 10.6002/ect.2022.0362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of thiopurine nucleotides into DNA and RNA. Thiopurine drug metabolites such as azathioprine and 6-mercaptopurine have been included in the lists of inosine triphosphate pyrophosphatase substrates. Inosine triphosphatase gene alterations are other pharmacogenetic sequence variants possibly involved in thiopurine metabolism. This study aimed to evaluate the possible association between ITPA 94C>A gene sequence variant (C-to-A substitution at nucleotide 94) in liver transplant recipients. MATERIALS AND METHODS The genotyping of ITPA 94C>A was evaluated by the polymerase chain reaction- restriction fragment length polymorphism method in 200 liver transplant recipients as well as 100 controls. Data were analyzed with SPSS statistical software. RESULTS This study showed statistically significant associations between the CA genotype of the ITPA 94C>A sequence variant and liver transplant in the rejection and nonrejection groups. Moreover, the results reported in this study showed no significant differences between sex, age, and blood group in patients with liver transplant (with or without transplant rejection). CONCLUSIONS Our results indicated that there were statistically significant associations of the CA genotype of ITPA 94C>A sequence variant with liver transplant in the rejection and nonrejection groups. Further studies are recommended.
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Affiliation(s)
- Mozhdeh Heidari
- From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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10
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Dewulf JP, Marie S, Nassogne MC. Disorders of purine biosynthesis metabolism. Mol Genet Metab 2022; 136:190-198. [PMID: 34998670 DOI: 10.1016/j.ymgme.2021.12.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/15/2021] [Accepted: 12/25/2021] [Indexed: 11/18/2022]
Abstract
Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.
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Affiliation(s)
- Joseph P Dewulf
- Laboratoire des Maladies Métaboliques Héréditaires/Biochimie Génétique et Centre de Dépistage Néonatal, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium; Institut des Maladies Rares, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium; Department of Biochemistry, de Duve Institute, UCLouvain, Brussels, Belgium.
| | - Sandrine Marie
- Laboratoire des Maladies Métaboliques Héréditaires/Biochimie Génétique et Centre de Dépistage Néonatal, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium; Institut des Maladies Rares, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium.
| | - Marie-Cécile Nassogne
- Institut des Maladies Rares, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium; Service de Neurologie Pédiatrique, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium.
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11
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Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides. Sci Rep 2022; 12:6408. [PMID: 35436992 PMCID: PMC9016069 DOI: 10.1038/s41598-022-10149-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/04/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractInosine triphosphate pyrophosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. In this work, we have characterized the Trypanosoma brucei ITPase ortholog (TbITPA). Recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. Immunolocalization analysis performed in bloodstream forms suggests that the primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. Even though ITPA-knockout bloodstream parasites are viable, they are more sensitive to inhibition of IMP dehydrogenase with mycophenolic acid, likely due to an expansion of IMP, the ITP precursor. On the other hand, TbITPA can also hydrolyze the activated form of the antiviral ribavirin although in this case, the absence of ITPase activity in the cell confers protection against this nucleoside analog. This unexpected phenotype is dependant on purine availability and can be explained by the fact that ribavirin monophosphate, the reaction product generated by TbITPA, is a potent inhibitor of trypanosomal IMP dehydrogenase and GMP reductase. In summary, the present study constitutes the first report on a protozoan inosine triphosphate pyrophosphatase involved in the removal of harmful deaminated nucleotides from the cytosolic pool.
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12
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Lee Y, Jang EJ, Yoon HY, Yee J, Gwak HS. Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2022; 15:ph15040416. [PMID: 35455413 PMCID: PMC9027773 DOI: 10.3390/ph15040416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.
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Affiliation(s)
- Yeonhong Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
- Department of Pharmacy, National Cancer Center, Goyang-si 10408, Korea
| | - Eun Jeong Jang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Ha-Young Yoon
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Jeong Yee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
| | - Hye-Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (Y.L.); (E.J.J.); (H.-Y.Y.); (J.Y.)
- Correspondence: ; Tel.: +82-2-3277-4376; Fax: +82-2-3277-3051
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Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis. THE PHARMACOGENOMICS JOURNAL 2022; 22:39-54. [PMID: 35034963 DOI: 10.1038/s41397-021-00255-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/24/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023]
Abstract
Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97-2.90, and OR: 2.43, 95%CI: 2.12-2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22-3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36-3.63, and OR: 2.82, 95%CI: 1.76-4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06-2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.
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14
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Yang QY, Hu YH, Guo HL, Xia Y, Zhang Y, Fang WR, Li YM, Xu J, Chen F, Wang YR, Wang TF. Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor. Front Pharmacol 2021; 12:771487. [PMID: 34955843 PMCID: PMC8696478 DOI: 10.3389/fphar.2021.771487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/24/2021] [Indexed: 11/25/2022] Open
Abstract
Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR’s clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient’s quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the CEP72 gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as CYP3A5, ABCB1, ABCC1, ABCC2, TTPA, ACTG1, CAPG, SYNE2, SLC5A7, COCH, and MRPL47, have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients’ quality of life.
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Affiliation(s)
- Qing-Yan Yang
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.,School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ya-Hui Hu
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hong-Li Guo
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Ying Xia
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Zhang
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wei-Rong Fang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yun-Man Li
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jing Xu
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Chen
- Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yong-Ren Wang
- Department of Hematology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Teng-Fei Wang
- Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN, United States
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15
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Pai AA, Mohan A, Benjamin ESB, Illangeswaran RSS, Xavier Raj I, Janet NB, Arunachalam AK, Kavitha ML, Kulkarni U, Devasia AJ, Fouzia NA, Abraham A, Srivastava A, George B, Mathews V, Korula A, Balasubramanian P. NUDT15 c.415C>T Polymorphism Predicts 6-MP Induced Early Myelotoxicity in Patients with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy. Pharmgenomics Pers Med 2021; 14:1303-1313. [PMID: 34629890 PMCID: PMC8495143 DOI: 10.2147/pgpm.s325813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/02/2021] [Indexed: 11/25/2022] Open
Abstract
PURPOSE Severe myelosuppression in patients with acute lymphoblastic leukemia (ALL) undergoing 6-MP-based maintenance therapy is attributed to TPMT gene polymorphisms, which is rare in Asian populations. This study aims to evaluate the role of selected polymorphisms in NUDT15, ITPA, and MRP4 genes in addition to TPMT in predicting 6-MP intolerance during ALL maintenance therapy. PATIENTS AND METHODS We screened for the presence of NUDT15*3 (c.415 C>T, rs116855232); MRP4 c.2269 C>T (rs3765534), ITPA c.94 C>A (rs1127354) polymorphisms in addition to TPMT *2 (rs1800462), *3A (*3B and *3C; rs1800460 and rs1142345) in ALL patients with documented severe neutropenia (cohort-1; n=42). These polymorphisms were then screened in a prospective cohort of ALL patients (cohort-2; n=133) and compared with 6-MP dose reduction, early/late myelotoxicity. RESULTS Nineteen (45%) patients in cohort-1 and 18 (14%) in cohort-2 had NUDT15 c.415 C>T variant while 4 (3%) patients in cohort-2 had TPMT*3C variant. Five (12%) in cohort-1 and 30 (24%) in cohort-2 had ITPA c.94 C>A variant while 9 (22%) and 15 (12%) had MRP4 c.2269 C>T variant in cohorts-1 and 2, respectively. All in cohort-1 and 36 (27%) in cohort-2 had severe myelotoxicity. Twenty-eight patients (66.6%) in cohort-1 and 40 (30%) patients in cohort-2 had significant 6-MP dose reduction. NUDT15 c.415 C>T variant explained severe myelotoxicity in 63% and 33% in cohort 1 and 2. TPMT*3C and ITPA c.94 C>A variants also explained myelotoxicity in cohort-2 (Median ANC: 376 vs 1014 mm3; p=0.04 and 776 vs 1023 mm3; p=0.04 respectively). NUDT15 c.415 C>T polymorphism explained significant myelotoxicity (507 vs 1298 mm3; p<0.0001) in the multivariate analysis as well (β=-0.314, p<0.0001). CONCLUSION NUDT15 c.415 C>T (15*3), TPMT*3C, as well as ITPA c.94 C>A and MRP4 c.2269 C>T polymorphisms explain hematotoxicities. Preemptive genotype-based (NUDT15*3, TPMT, ITPA c.94 C>A) 6-MP dosing could improve the outcome after maintenance therapy.
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Affiliation(s)
- Aswin Anand Pai
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Ajith Mohan
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | | | | | - Infencia Xavier Raj
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Nancy Beryl Janet
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | | | - M L Kavitha
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Uday Kulkarni
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Anup J Devasia
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - N A Fouzia
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Aby Abraham
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Alok Srivastava
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Biju George
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
| | - Anu Korula
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, India
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16
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Waldenström J, Kåberg M, Alanko Blomé M, Widell A, Björkman P, Nilsson S, Hammarberg A, Weiland O, Nyström K, Lagging M. Absence of interferon-λ 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection. Scand J Gastroenterol 2021; 56:855-861. [PMID: 34034600 DOI: 10.1080/00365521.2021.1925956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Absence of a functional interferon-λ 4 (IFN-λ4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. MATERIALS AND METHODS Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. RESULTS The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-λ4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and ΔGrs1368234815 respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-λ4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-λ4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). CONCLUSIONS Absence of IFN-λ4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-λ4, reduced ITPase activity improved outcome.
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Affiliation(s)
- Jesper Waldenström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Martin Kåberg
- Department of Medicine, Huddinge Division of Infection and Dermatology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | | | - Anders Widell
- Department of Clinical Virology, Department of Translational Medicine, Lund University, Lund, Sweden
| | - Per Björkman
- Department of Clinical Infection Medicine, Lund University, Lund, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology, Sweden.,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden
| | - Anders Hammarberg
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.,Stockholm Centre for Dependency Disorders, Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
| | - Ola Weiland
- Department of Medicine, Huddinge Division of Infection and Dermatology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - Kristina Nyström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Microbiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Microbiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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Lee JM, Shim YJ, Kim DH, Jung N, Ha JS. The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia. CHILDREN-BASEL 2021; 8:children8030224. [PMID: 33804051 PMCID: PMC7998516 DOI: 10.3390/children8030224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.
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Affiliation(s)
- Jae Min Lee
- Department of Pediatrics, Yeungnam University College of Medicine, Daegu 42415, Korea;
| | - Ye Jee Shim
- Department of Pediatrics, Keimyung University School of Medicine, Daegu 42601, Korea; (Y.J.S.); (N.J.)
| | - Do-Hoon Kim
- Department of Laboratory Medicine, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Nani Jung
- Department of Pediatrics, Keimyung University School of Medicine, Daegu 42601, Korea; (Y.J.S.); (N.J.)
| | - Jung-Sook Ha
- Department of Laboratory Medicine, Keimyung University School of Medicine, Daegu 42601, Korea;
- Correspondence: ; Tel.: +82-53-258-7938
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18
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Koga Y, Tsuchimoto D, Hayashi Y, Abolhassani N, Yoneshima Y, Sakumi K, Nakanishi H, Toyokuni S, Nakabeppu Y. Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy. JCI Insight 2020; 5:140229. [PMID: 33208550 PMCID: PMC7710303 DOI: 10.1172/jci.insight.140229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 10/15/2020] [Indexed: 11/17/2022] Open
Abstract
Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell-specific Itpa-conditional KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure.
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Affiliation(s)
- Yuichiro Koga
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
| | - Daisuke Tsuchimoto
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
| | - Yoshinori Hayashi
- Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Nona Abolhassani
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
| | - Yasuto Yoneshima
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
| | - Kunihiko Sakumi
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
| | - Hiroshi Nakanishi
- Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima, Japan
| | - Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and
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19
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Labarile N, Ghosh S, Ng SC, Walters J, Iacucci M. Tests that now deserve to be more widely adopted in IBD clinical practice. Therap Adv Gastroenterol 2020; 13:1756284820944088. [PMID: 32782481 PMCID: PMC7385848 DOI: 10.1177/1756284820944088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/30/2020] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel diseases are chronic relapsing immune-mediated diseases of the intestinal tract with multifaceted manifestations and treatment related morbidity. Faecal and blood tests, radiological, endoscopic and histologic investigations are now widely used for managing both ulcerative colitis and Crohn's disease. Over the years, a number of new investigations have been proposed but not widely adopted yet. Patients with Crohn's disease may have multiple causes of diarrhoea, not always attributable to disease exacerbation, but sometimes linked to bile acid malabsorption; we have a reliable serum test, C4, that allows us to recognize and treat this cause of diarrhoea efficaciously and not empirically, but it is not available or used widely. There is genetic inter-individual variability in drug responses, in terms of both efficacy and toxicity, leading to high rates of therapeutic failure. Patients treated with thiopurine or, more rarely, 5-aminosalicylic acid may suffer from unpredictable and serious adverse events, some of these with pathogenesis related to genetic variants: myelosuppression, acute pancreatitis and nephrotoxicity. The identification of pre-treatment genetic tests can optimize therapeutic choice and avoid adverse events. With regard to biological drugs, patients can experience primary non-response or loss of response due to induction of immune responses to the drugs affecting drug efficacy and determining hypersensitivity reactions. We have specifically reviewed a number of investigations, whose use is currently limited, and highlighted four tests that deserve to be more widely incorporated in clinical practice as these could improve medical decision-making and patient outcomes.
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Affiliation(s)
| | - Subrata Ghosh
- Institute Translational of Medicine, Institute of Immunology and Immunotherapy and NIHR Birmingham Biomedical Research Centre, University Hospitals NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Julian Walters
- Division of Digestive Diseases, Imperial College London, Imperial College Healthcare, London, UK
| | - Marietta Iacucci
- Institute Translational of Medicine, Institute of Immunology and Immunotherapy and NIHR Birmingham Biomedical Research Centre, University Hospitals NHS Foundation Trust and University of Birmingham, Birmingham, UK
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20
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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21
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Zhou Y, Wang L, Zhai XY, Wen L, Tang F, Yang F, Liu XT, Dong L, Zhi LJ, Shi HY, Hao GX, Zheng Y, Jacqz-Aigrain E, Wang TY, Zhao W. Precision therapy of 6-mercaptopurine in Chinese children with acute lymphoblastic leukaemia. Br J Clin Pharmacol 2020; 86:1519-1527. [PMID: 32077136 DOI: 10.1111/bcp.14258] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 01/02/2023] Open
Abstract
AIMS Chinese children are more susceptible to the development of thiopurine-induced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship through exploration of pharmacogenetic factors involved in the thiopurine-induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL). METHODS Blood samples were obtained from ALL children treated with 6-MP. We determined the metabolite steady-state concentrations of 6-MP in red blood cells (RBCs) by using high-performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform. RESULTS Sixty children afflicted by ALL who received 6-MP treatment were enrolled in this study. The median concentration of 6-thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 108 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 108 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 108 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50-fold and 5.80-fold higher risk of leukopenia, respectively. MTHFR rs1801133 variants were found to have had a 4.46-fold significantly higher risk of hepatotoxicity vs wild-type genotype. CONCLUSION Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese paediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6-MP maintenance therapy.
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Affiliation(s)
- Yue Zhou
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Li Wang
- Department of Paediatric Haematology-Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Xiao-Ying Zhai
- Department of Paediatric Haematology-Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Li Wen
- Department of Paediatric Haematology-Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Fang Tang
- Big data Center, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Fan Yang
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xi-Ting Liu
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Lei Dong
- Department of Pharmacy, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Li-Juan Zhi
- Department of Paediatric Haematology-Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Hai-Yan Shi
- Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Guo-Xiang Hao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yi Zheng
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | | | - Tian-You Wang
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Wei Zhao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.,Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
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Löffler M, Carrey EA, Knecht W. The pathway to pyrimidines: The essential focus on dihydroorotate dehydrogenase, the mitochondrial enzyme coupled to the respiratory chain. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2020; 39:1281-1305. [PMID: 32043431 DOI: 10.1080/15257770.2020.1723625] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This paper is based on the Anne Simmonds Memorial Lecture, given by Monika Löffler at the International Symposium on Purine and Pyrimidine Metabolism in Man, Lyon 2019. It is dedicated to H. Anne Simmonds (died 2010) - a founding member of the ESSPPMM, since 2003 Purine and Pyrimidine Society - and her outstanding contributions to the identification and study of inborn errors of purine and pyrimidine metabolism. The distinctive intracellular arrangement of pyrimidine de novo synthesis in higher eukaryotes is important to cells with a high demand for nucleic acid synthesis. The proximity of the enzyme active sites and the resulting channeling in CAD and UMP synthase is of kinetic benefit. The intervening enzyme dihydroorotate dehydrogenase (DHODH) is located in the mitochondrion with access to the ubiquinone pool, thus ensuring efficient removal of redox equivalents through the constitutive activity of the respiratory chain, also a mechanism through which the input of 2 ATP for carbamylphosphate synthesis is balanced by Oxphos. The obligatory contribution of O2 to de novo UMP synthesis means that DHODH has a pivotal role in adapting the proliferative capacity of cells to different conditions of oxygenation, such as hypoxia in growing tumors. DHODH also is a validated drug target in inflammatory diseases. This survey of selected topics of personal interest and reflection spans some 40 years of our studies from tumor cell cultures under hypoxia to in vitro assays including purification from mitochondria, localization, cloning, expression, biochemical characterization, crystallisation, kinetics and inhibition patterns of eukaryotic DHODH enzymes.
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Affiliation(s)
- Monika Löffler
- Institute of Physiological Chemistry, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | | | - Wolfgang Knecht
- Department of Biology & Lund Protein Production Platform, Lund University, Lund, Sweden
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23
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Senthilvelan A, Shanmugasundaram M, Kore AR. An efficient protection-free chemical synthesis of inosine 5'-nucleotides. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2020; 39:829-837. [PMID: 31997708 DOI: 10.1080/15257770.2019.1708388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
A facile, straightforward, reliable, and efficient chemical synthesis of inosine nucleotides such as inosine-5'-monophosphate, inosine-5'-diphosphate, and inosine-5'-triphosphate, starting from inosine is delineated. The inosine-5'-monophosphate is achieved by the highly regioselective monophosphorylation of inosine using the Yoshikawa procedure. The inosine-5'-diphosphate is obtained by the coupling reaction of tributylammonium phosphate with an activated inosine-5'-monophosphate using zinc chloride as a catalyst. The inosine-5'-triphosphate is efficiently achieved by the improved "one-pot, three-step" Ludwig synthetic strategy. In all the cases, the resulting final product is isolated in good yields with high purity (>99.5%).
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Affiliation(s)
| | | | - Anilkumar R Kore
- Life Sciences Solutions Group, Thermo Fisher Scientific, Austin, TX, USA
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24
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Wahlund M, Nilsson A, Kahlin AZ, Broliden K, Myrberg IH, Appell ML, Berggren A. The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia. J Pediatr 2020; 216:150-157.e1. [PMID: 31635813 DOI: 10.1016/j.jpeds.2019.09.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 08/05/2019] [Accepted: 09/11/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL). STUDY DESIGN The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing. RESULTS TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P < .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia. CONCLUSIONS White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.
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Affiliation(s)
- Martina Wahlund
- Infectious Disease Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Nilsson
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Anna Zimdahl Kahlin
- Division of Drug Research, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden
| | - Kristina Broliden
- Infectious Disease Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden
| | - Ida Hed Myrberg
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Malin Lindqvist Appell
- Division of Drug Research, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden
| | - Anna Berggren
- Infectious Disease Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
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26
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Tanaka Y, Inoue A, Mizunuma T, Matsumura H, Yokomori H, Komiyama T, Otori K. Tolerability of Erythrocyte Ribavirin Triphosphate Concentrations Depends on the ITPA Genotype. Ther Drug Monit 2019; 41:497-502. [PMID: 30817703 DOI: 10.1097/ftd.0000000000000626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Ribavirin (RBV) is an antiviral drug that is part of the current standard therapy for chronic hepatitis C (CHC). It is enzymatically converted to ribavirin triphosphate (RTP) that inhibits the activity of viral RNA polymerase, thereby preventing viral replication. However, one of its adverse effects includes hemolytic anemia that limits its application. The variant of ITPA (inosine triphosphatase), which dephosphorylates inosine triphosphate to inosine monophosphate, is a protective factor for RBV-induced anemia. RTP is an important metabolite required for ribavirin action. This study evaluated the time-dependent association of RTP concentrations in erythrocytes, RBV-induced toxicity, and virological response to RBV treatment for hepatitis C. METHODS A total of 28 Japanese patients with CHC were treated with RBV/peg-interferon/simeprevir or RBV/sofosbuvir and were genotyped for ITPA variants (rs1127354 and rs7270101). We measured RTP concentrations in erythrocytes in a total of 76 samples collected at 4, 8, and 12 weeks from the initiation of treatment. RESULTS The ITPA rs1127354 variant was found in 7 patients. This was associated with significantly higher RTP concentrations in erythrocytes than in the wild-type patients (P < 0.001). Moreover, a significant correlation was observed between RTP concentrations and decline in hemoglobin (Hb) levels from baseline values in ITPA wild type and rs1127354 variant 12 weeks after treatment initiation (P < 0.01; r = -0.618 and -0.967, respectively). Multiple regression analysis revealed that ITPA genotype and erythrocyte RTP concentrations were major factors associated with reduced Hb levels in RBV therapy for CHC. However, we did not find any association between erythrocyte concentrations and virological response. CONCLUSIONS The increased tolerability to RTP concentrations in erythrocytes in the ITPA variant rs1127354 plays a role in preventing RBV-induced severe anemia in this ITPA variant.
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Affiliation(s)
- Yoichi Tanaka
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
| | - Akiko Inoue
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
| | - Tomohiko Mizunuma
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
| | - Haruka Matsumura
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
| | - Hiroaki Yokomori
- Department of General Internal Medicine, Kitasato University Medical Center, Tokyo, Japan
| | - Takako Komiyama
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
| | - Katsuya Otori
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University
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Franca R, Zudeh G, Pagarin S, Rabusin M, Lucafò M, Stocco G, Decorti G. Pharmacogenetics of thiopurines. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:256-270. [PMID: 35582727 PMCID: PMC8992634 DOI: 10.20517/cdr.2019.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/16/2019] [Accepted: 03/21/2019] [Indexed: 11/12/2022]
Abstract
Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2, have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.
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Affiliation(s)
- Raffaella Franca
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Giulia Zudeh
- PhD Course in Reproductive and Developmental Sciences, University of Trieste, Trieste 34127, Italy
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Sofia Pagarin
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
| | - Marco Rabusin
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
| | - Marianna Lucafò
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
- Experimental and Clinical Pharmacology Unit, Centro di riferimento oncologico, I.R.C.C.S., Aviano 33081, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Giuliana Decorti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy
- Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy
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Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, Stocco G. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2018; 14:1209-1223. [PMID: 30465611 DOI: 10.1080/17425255.2018.1551876] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.
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Affiliation(s)
- Marianna Lucafò
- a Experimental and Clinical Pharmacology Unit , National Cancer Institute - Centro di Riferimento Oncologico , Aviano , Italy
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
| | - Raffaella Franca
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Davide Selvestrel
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Debora Curci
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Letizia Pugnetti
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Giuliana Decorti
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Gabriele Stocco
- e Department of Life Sciences , University of Trieste , Trieste , Italy
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Lim SZ, Chua EW. Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring. Front Pharmacol 2018; 9:1107. [PMID: 30349479 PMCID: PMC6186994 DOI: 10.3389/fphar.2018.01107] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022] Open
Abstract
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
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Affiliation(s)
| | - Eng Wee Chua
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Nyström K, Wanrooij PH, Waldenström J, Adamek L, Brunet S, Said J, Nilsson S, Wind-Rotolo M, Hellstrand K, Norder H, Tang KW, Lagging M. Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus. J Virol 2018; 92:e01087-18. [PMID: 30045981 PMCID: PMC6146798 DOI: 10.1128/jvi.01087-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/17/2018] [Indexed: 12/19/2022] Open
Abstract
A third of humans carry genetic variants of the ITP pyrophosphatase (ITPase) gene (ITPA) that lead to reduced enzyme activity. Reduced ITPase activity was earlier reported to protect against ribavirin-induced hemolytic anemia and to diminish relapse following ribavirin and interferon therapy for hepatitis C virus (HCV) genotype 2 or 3 infections. While several hypotheses have been put forward to explain the antiviral actions of ribavirin, details regarding the mechanisms of interaction between reduced ITPase activity and ribavirin remain unclear. The in vitro effect of reduced ITPase activity was assessed by means of transfection of hepatocytes (Huh7.5 cells) with a small interfering RNA (siRNA) directed against ITPA or a negative-control siRNA in the presence or absence of ribavirin in an HCV culture system. Low ribavirin concentrations strikingly depleted intracellular GTP levels in HCV-infected hepatocytes whereas higher ribavirin concentrations induced G-to-A and C-to-U single nucleotide substitutions in the HCV genome, with an ensuing reduction of HCV RNA expression and HCV core antigen production. Ribavirin triphosphate (RTP) was dephosphorylated in vitro by recombinant ITPase to a similar extent as ITP, a naturally occurring substrate of ITPase, and reducing ITPA expression in Huh 7.5 cells by siRNA increased intracellular levels of RTP in addition to increasing HCV mutagenesis and reducing progeny virus production. Our results extend the understanding of the biological impact of reduced ITPase activity, demonstrate that RTP is a substrate of ITPase, and may point to personalized ribavirin dosage according to ITPA genotype in addition to novel antiviral strategies.IMPORTANCE This study highlights the multiple modes of action of ribavirin, including depletion of intracellular GTP and increased hepatitis C virus mutagenesis. In cell culture, reduced ITP pyrophosphatase (ITPase) enzyme activity affected the intracellular concentrations of ribavirin triphosphate (RTP) and augmented the impact of ribavirin on the mutation rate and virus production. Additionally, our results imply that RTP, similar to ITP, a naturally occurring substrate of ITPase, is dephosphorylated in vitro by ITPase.
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Affiliation(s)
- Kristina Nyström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Paulina H Wanrooij
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - Jesper Waldenström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ludmila Adamek
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sofia Brunet
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Joanna Said
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
- Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Kristoffer Hellstrand
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Helene Norder
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ka-Wei Tang
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Tanaka Y, Yokomori H, Otori K. Induction of inosine triphosphatase activity during ribavirin treatment for chronic hepatitis C. Clin Chim Acta 2018; 482:16-20. [PMID: 29580856 DOI: 10.1016/j.cca.2018.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/17/2018] [Accepted: 03/18/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND Ribavirin (RBV) is an antiviral agent and the primary component for chronic hepatitis C (CHC) therapy. Hemolytic anemia is limitation for RBV treatment. Inosine triphosphatase (ITPA) activity has been associated with severity of RBV-induced anemia. However, changes in ITPA activity during CHC therapy are unknown. The aim of this study was to measure the time-dependent change in ITPA activity over the RBV treatment. METHODS Forty-two patients with CHC were evaluated for ITPA activity over the course of RBV treatment. RESULTS The median value of ITPA activity at start of RBV treatment was 134.2 μmol/h/g hemoglobin (Hb; range, 26.3-251.0 μmol/h/g Hb). The ITPA activity values at 4, 8, and 12 weeks during RBV treatment were 143.2, 202.2, and 225.7 μmol/h/g Hb, respectively, and these ITPA values were significantly elevated compared with the start of treatment (p < 0.001). In patients with ITPA variants, patients with anemia (Hb < 10 g/dL) had greater elevated ITPA activities compared with patients without anemia at 12 weeks. CONCLUSION Our findings indicate that ITPA activities are elevated with RBV therapy, and this elevation may be a risk of anemia in late therapeutic phase in patients that began with low ITPA activity.
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Affiliation(s)
- Yoichi Tanaka
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Japan.
| | - Hiroaki Yokomori
- Department of General Internal Medicine, Kitasato University Medical Center, Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Japan
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Vasanthakumar A, Davis JW, Abunimeh M, Söderholm J, Zha J, Dumas EO, Cohen DE, Waring JF, Lagging M. Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens. PLoS One 2018; 13:e0198296. [PMID: 29851985 PMCID: PMC5979032 DOI: 10.1371/journal.pone.0198296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/16/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections. AIM To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens. METHODS In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV. RESULTS Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels. CONCLUSIONS Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.
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Affiliation(s)
| | - Justin W. Davis
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Manal Abunimeh
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Jonas Söderholm
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Jiuhong Zha
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Emily O. Dumas
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Daniel E. Cohen
- AbbVie Inc., North Chicago, Illinois, United States of America
| | | | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
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Adam de Beaumais T, Jacqz-Aigrain E. Pharmacogenetics: Applications to Pediatric Patients. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 83:191-215. [PMID: 29801575 DOI: 10.1016/bs.apha.2018.04.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Individual genomic differences may affect drug disposition and effects of many drugs, and identification of biomarkers are crucial to personalize dosage and optimize response. In children, developmental changes associated with growth and maturation translate into different relationships between genotype and phenotype and different responses to treatment compared to adults. This review aims to summarize some developmental aspects of pharmacogenetics, based on practical examples.
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Affiliation(s)
- Tiphaine Adam de Beaumais
- Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France
| | - Evelyne Jacqz-Aigrain
- Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France; University Paris Diderot Sorbonne Paris Cité, Paris, France; Clinical Investigation Center CIC1426, INSERM, Paris, France.
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ITPA Activity in Adults and Children Treated With or Without Azathioprine: Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications. Ther Drug Monit 2018. [PMID: 28650902 DOI: 10.1097/ftd.0000000000000430] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data are available on its role on thiopurine metabolites. The ability of ITPA to modify the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) therapy in relation to thiopurine S-methyltransferase (TPMT) activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites. METHODS ITPA activity was determined in 183 adults and 138 children with or without AZA therapy. 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in red blood cells. Using the Gaussian mixture model, distribution of ITPA activity was evaluated. Intraindividual variability and influence of age, sex, AZA treatment and associated co-medications on ITPA activity were also assessed. RESULTS This retrospective study shows a quadrimodal distribution in ITPA activity. No influence of age, sex, AZA therapy, and co-medications was found. In adults, ITPA activity was not significantly associated with 6-TGN or 6-MeMPN concentrations, whereas a weak negative correlation was observed with 6-MeMPN levels in pediatric populations (rs = -0.261; P = 0.024). A weak positive correlation was observed between ITPA and TPMT activities in children (rs = 0.289; P = 0.001). CONCLUSIONS ITPA activity was poorly influenced by nongenetic parameters and has no influence on 6-TGN and 6-MeMPN concentrations in adults and only a weak correlation with 6-MeMPN and TPMT activity in children. These results demonstrate that ITPA is not a rate-limiting enzyme in the formation of 6-TGN but suggest that a decrease in ITPA activity in children may be a risk factor for accumulation of 6-MeMPN in cells.
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Charbgoo F, Behmanesh M, Nikkhah M, Kane EG. RNAi mediated gene silencing of ITPA using a targeted nanocarrier: Apoptosis induction in SKBR3 cancer cells. Clin Exp Pharmacol Physiol 2018; 44:888-894. [PMID: 28464292 DOI: 10.1111/1440-1681.12776] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 04/08/2017] [Accepted: 04/13/2017] [Indexed: 11/28/2022]
Abstract
A pure nucleotide pool is required for high-fidelity DNA replication and prevention of carcinogenesis in living cells. Human inosine triphosphatase (ITPase), encoded by the ITPA gene, plays a critical role in maintaining the purity of the cellular nucleotide pool by excluding nucleotides that enhance mutagenesis. ITPase is a nucleoside triphosphate pyrophosphatase that hydrolyzes the non-canonical nucleotides inosine triphosphate (ITP) and xanthine triphosphate (XTP). The monophosphate products of ITPase reactions are subsequently excluded from the nucleotide pool and the improper substitution of ITP and XTP into DNA and RNA is prevented. Previous studies show that deficiency in ITPA can suppress cellular growth and enhance DNA instability. In this study, we evaluated the influence of effective ITPA down-regulation on the induction of apoptosis in a human cancer cell line using folate-single wall nanotubes (SWNT) as a targeted nanocarrier. We assessed whether SWNT enhances IPTA-siRNA transfection efficiency in cancer cells using folate as a homing device. Since folate receptor is considerably overexpressed in cancer cells, conjugation of SWNTs to folate could enhance their cancer-specific penetrance. We found that nanocarrier mediated ITPA-siRNA transfection into SKBR3 cells caused significant reduction of ITPA mRNA expression level and complete down-regulation of the ITPase protein product. The silencing of ITPA led to promotion of apoptosis in SWNT-treated SKBR3 cancer cells.
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Affiliation(s)
- Fahimeh Charbgoo
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehrdad Behmanesh
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.,Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Nikkhah
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Eric G Kane
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA
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Citterio-Quentin A, Moulsma M, Gustin MP, Lachaux A, Boulieu R. ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response. Basic Clin Pharmacol Toxicol 2018; 122:588-595. [PMID: 29327413 DOI: 10.1111/bcpt.12958] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/27/2017] [Indexed: 12/13/2022]
Abstract
Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.
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Affiliation(s)
- Antony Citterio-Quentin
- UMR CNRS 5305, Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Université de Lyon, Université Lyon 1, Lyon, France.,Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
| | - Mustapha Moulsma
- Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
| | - Marie-Paule Gustin
- Emerging pathogen Laboratory - Fondation Mérieux, Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France
| | - Alain Lachaux
- Pediatric Gastroenterology Unit, Civil Hospices of Lyon, Hôpital Femme-Mère-Enfant (HFME), Lyon, France
| | - Roselyne Boulieu
- UMR CNRS 5305, Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Université de Lyon, Université Lyon 1, Lyon, France.,Edouard Herriot Hospital, Laboratory of Medical Biology Multi Sites of the University Hospital of Lyon, Pharmaco-Toxicology Unit, Civil Hospices of Lyon, Lyon, France
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Peltenburg NC, Bierau J, Bakker JA, Schippers JA, Lowe SH, Paulussen ADC, van den Bosch BJC, Leers MPG, Hansen BE, Verbon A. Erythrocyte Inosine triphosphatase activity: A potential biomarker for adverse events during combination antiretroviral therapy for HIV. PLoS One 2018; 13:e0191069. [PMID: 29329318 PMCID: PMC5766130 DOI: 10.1371/journal.pone.0191069] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 12/26/2017] [Indexed: 12/30/2022] Open
Abstract
The purine analogues tenofovir and abacavir are precursors of potential substrates for the enzyme Inosine 5'-triphosphate pyrophosphohydrolase (ITPase). Here, we investigated the association of ITPase activity and ITPA genotype with the occurrence of adverse events (AEs) during combination antiretroviral therapy (cART) for human immunodeficiency virus (HIV) infection. In 393 adult HIV-seropositive patients, AEs were defined as events that led to stop of cART regimen. ITPase activity ≥4 mmol IMP/mmol Hb/hour was considered as normal. ITPA genotype was determined by testing two ITPA polymorphisms: c.94C>A (p.Pro32Thr, rs1127354) and c.124+21A>C (rs7270101). Logistic regression analysis determined odds ratios for developing AEs. In tenofovir-containing regimens decreased ITPase activity was associated with less AEs (p = 0.01) and longer regimen duration (p = 0.001). In contrast, in abacavir-containing regimens decreased ITPase activity was associated with more AEs (crude p = 0.02) and increased switching of medication due to AEs (p = 0.03). ITPA genotype wt/wt was significantly associated with an increase in the occurrence of AEs in tenofovir-containing regimens. Decreased ITPase activity seems to be protective against occurrence of AEs in tenofovir-containing cART, while it is associated with an increase in AEs in abacavir-containing regimens.
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Affiliation(s)
- N. Chantal Peltenburg
- Department of Internal medicine, Division Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jörgen Bierau
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jaap A. Bakker
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jolanda A. Schippers
- Department of Integrated Care, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Selwyn H. Lowe
- Department of internal medicine, Division Infectious Diseases, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Medical Microbiology, School of CAPHRI, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Aimée D. C. Paulussen
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | - Mathie P. G. Leers
- Department of Clinical Chemistry & Hematology, Zuyderland Medical Center, Heerlen, The Netherlands
| | - Bettina E. Hansen
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Annelies Verbon
- Department of Internal medicine, Division Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
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Mollaahmadi F, Moini A, Salman Yazdi R, Behmanesh M. The rs1127354 Polymorphism in ITPA Is Associated with Susceptibility to Infertility. CELL JOURNAL 2018; 20:73-77. [PMID: 29308621 PMCID: PMC5759682 DOI: 10.22074/cellj.2018.4255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 01/21/2017] [Indexed: 12/29/2022]
Abstract
Objective Infertility is a common human disorder which is defined as the failure to conceive for a period of 12 months
without contraception. Many studies have shown that the outcome of fertility could be affected by DNA damage. We
attempted to examine the association of two SNPs (rs1127354 and rs7270101) in ITPA, a gene encoding a key factor
in the repair system, with susceptibility to infertility.
Materials and Methods This was a case-control study of individuals with established infertility. Blood samples were
obtained from 164 infertile patients and 180 ethnically matched fertile controls. Total genomic DNA were extracted
from whole blood using the standard salting out method, and stored at -20˚C. Genotyping were based on mismatch
polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in which PCR products were
digested with the XmnI restriction enzyme and run on a 12% polyacrylamide gel.
Results All genotype frequencies in the control group were in Hardy-Weinberg equilibrium. A significant association
(in allelic, recessive and dominant genotypic models) was observed between infertile patients and healthy controls
based on rs1127354 (P=0.0001), however, no significant association was detected for rs7270101. Also, gender
stratification and analysis of different genotype models did not lead to a significant association for this single-
nucleotide polymorphis (SNP).
Conclusion ITPA is likely to be a genetic determinant for decreased fertility. To the best of our knowledge, this is the
first report demonstrating this association, however, given the small sample size and other limitations, genotyping of
this SNP is recommended to be carried out in different populations with more samples.
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Affiliation(s)
- Fahimeh Mollaahmadi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.,Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Ashraf Moini
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Reza Salman Yazdi
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mehrdad Behmanesh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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Ji D, Stepchenkova EI, Cui J, Menezes MR, Pavlov YI, Kool ET. Measuring deaminated nucleotide surveillance enzyme ITPA activity with an ATP-releasing nucleotide chimera. Nucleic Acids Res 2017; 45:11515-11524. [PMID: 29036687 PMCID: PMC5714213 DOI: 10.1093/nar/gkx774] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/23/2017] [Indexed: 01/24/2023] Open
Abstract
Nucleotide quality surveillance enzymes play important roles in human health, by detecting damaged molecules in the nucleotide pool and deactivating them before they are incorporated into chromosomal DNA or adversely affect metabolism. In particular, deamination of adenine moiety in (deoxy)nucleoside triphosphates, resulting in formation of (d)ITP, can be deleterious, leading to DNA damage, mutagenesis and other harmful cellular effects. The 21.5 kDa human enzyme that mitigates this damage by conversion of (d)ITP to monophosphate, ITPA, has been proposed as a possible therapeutic and diagnostic target for multiple diseases. Measuring the activity of this enzyme is useful both in basic research and in clinical applications involving this pathway, but current methods are nonselective and are not applicable to measurement of the enzyme from cells or tissues. Here, we describe the design and synthesis of an ITPA-specific chimeric dinucleotide (DIAL) that replaces the pyrophosphate leaving group of the native substrate with adenosine triphosphate, enabling sensitive detection via luciferase luminescence signaling. The probe is shown to function sensitively and selectively to quantify enzyme activity in vitro, and can be used to measure the activity of ITPA in bacterial, yeast and human cell lysates.
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Affiliation(s)
- Debin Ji
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Elena I Stepchenkova
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.,Department of Genetics and Biotechnology, Saint-Petersburg State University, St Petersburg, 199034, Russia.,Saint-Petersburg Branch of Vavilov Institute of General Genetics, RAS, St Petersburg, 199034, Russia
| | - Jian Cui
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Miriam R Menezes
- Department of Neurosurgery, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Youri I Pavlov
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.,Departments of Biochemistry and Molecular Biology; Microbiology and Pathology; Genetics Cell Biology and Anatomy; University of Nebraska Medical Center, Omaha, NE 61818, USA
| | - Eric T Kool
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
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Rufini S, Ciccacci C, Novelli G, Borgiani P. Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease. Pharmacogenomics 2017; 18:1095-1114. [PMID: 28686143 DOI: 10.2217/pgs-2017-0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
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Affiliation(s)
- Sara Rufini
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
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Liu Z, Wang S, Qi W, Wang X, Sun D, Wang H, Zhang Y, Li Z, Zhu L, Zhao P, Guo H, Zhou C, Wang J. The relationship between ITPA rs1127354 polymorphisms and efficacy of antiviral treatment in Northeast Chinese CHC patients. Medicine (Baltimore) 2017; 96:e7554. [PMID: 28723780 PMCID: PMC5521920 DOI: 10.1097/md.0000000000007554] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 06/22/2017] [Accepted: 06/26/2017] [Indexed: 01/04/2023] Open
Abstract
This prospective study investigated the relationship between 2 inosine triphosphatase (ITPA) polymorphisms (rs7270101 and rs1127354) and the efficacy of ribavirin-based antiviral therapy in hepatitis C virus (HCV)-infected Chinese patients.A total of 906 patients diagnosed with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin combination therapy between January 2011 and January 2014 from 5 hepatitis centers in Northeast China were enrolled. The patients were divided into genotype 1 and non-genotype 1 groups according to the genotype of infected HCV. ITPA single nucleotide polymorphism (SNP) genotyping was performed for all patients. Ribavirin-induced hemolytic anemia and virological response (VR) were monitored during treatment and follow-up. Multivariate regression analysis was used to analyze the predictors for sustained virological response (SVR).IPTA rs7270101 variants were not detected. IPTA rs1127354 variants were detected and showed no difference between the genotype 1 and non-genotype 1 groups. IPTA rs1127354 genotype CC was related to a higher incidence of ribavirin-induced hemolytic anemia. For patients who received >80% of the planned ribavirin dose, rs1127354 variants and related ITPase were related to better SVR. Multivariate analysis showed that IPTA rs1127354 non-genotype CC, HCV genotype, a baseline HCV RNA level <4 × 10 IU/mL, IL-28B rs12979860 genotype CC, and low liver fibrosis were independent predictors for SVR during the combination therapy.IPTA rs1127354 variants and related ITPase were not only related with ribavirin-induced hemolytic anemia but also directly affected the SVR to PEG-IFN plus ribavirin combination therapy in Chinese HCV-infected patients.
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Affiliation(s)
- Zhenhua Liu
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Song Wang
- Department of Urology of First Hospital affiliated to Jilin University, Changchun
| | - Wenqian Qi
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Xu Wang
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Derong Sun
- Department of Digestive of the Second Hospital of Daqing
| | - Hongguang Wang
- Department of Digestive of the People's Hospital of Jilin City
| | - Yonggui Zhang
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Zhongxie Li
- Department of Digestive of the People's Hospital of Hunchun City, Jilin
| | - Liying Zhu
- Department of Infectious Diseases of the Fourth Hospital of Harbin Medical University, Heilongjiang, China
| | - Ping Zhao
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Honghua Guo
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Changyu Zhou
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
| | - Jiangbin Wang
- Department of Digestive of China-Japan Union Hospital affiliated to Jilin University
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El Raziky M, Zayed NA, Abdel Baki A, Mansour SA, Shahin RMH. ITPA gene polymorphism (94C>A) effects on ribavirin-induced anemia during therapy in Egyptian patients with chronic hepatitis C. J Med Virol 2017; 89:1823-1829. [PMID: 28480960 DOI: 10.1002/jmv.24844] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 04/11/2017] [Indexed: 12/13/2022]
Abstract
Inosine triphosphatase (ITPA) gene variants can protect against ribavirin (RBV)-induced anemia in patients treated for chronic hepatitis C. The aim of this study was to determine the relationship between genetic variants of ITPA polymorphism, anemia, RBV dose reduction, and treatment response in hepatitis C virus (HCV)-infected patients. This study was conducted on 97 Egyptian chronic HCV patients who were scheduled for pegylated-interferon (PEG-INF) /RBV therapy. ITPA genotypes rs1127354 were determined by Real Time PCR melting curve analysis. Effects of ITPA polymorphism on hemoglobin (Hb) levels, RBV dose reduction and treatment response were analyzed. The homozygous wild genotype (CC) was associated with Hb reduction at week 4 (P = 0.004). The minor allele protected against Hb reduction. No association with sustained virological response was observed (P = 0.492). Female gender; lower baseline Hb and higher baseline WBC were associated with week 4 anemia (P = 0.04; P = 0.023; 0.033, respectively). The ITPA gene polymorphism rs1127354 heterozygous genotype (CA) may influence Hb levels and protect against hemolytic anemia during RBV-containing regimens for HCV. However, such findings were not significantly related to treatment outcomes. Patients with wild ITPA genotype (CC) experienced a more Hb drop and RBV dose reductions more frequently.
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Affiliation(s)
- Maissa El Raziky
- Department of Endemic Medicine and Hepatology, Kasr Al Ainy Hospital, School of Medicine, Cairo University, Cairo, Egypt
| | - Naglaa A Zayed
- Department of Endemic Medicine and Hepatology, Kasr Al Ainy Hospital, School of Medicine, Cairo University, Cairo, Egypt
| | - Amin Abdel Baki
- Department of Tropical Medicine, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Shimaa A Mansour
- Department of Tropical Medicine, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Rasha M H Shahin
- Department of Clinical Pathology, Kasr Al Ainy, School of Medicine, Cairo University, Cairo, Egypt
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Gonzalez-Aldaco K, Rebello Pinho JR, Panduro A, Martinez-Lopez E, Gleyzer K, Fierro N, Roman S, Kneteman NM, Marotta PJ, Al-Judaibi B. High Prevalence of ITPA Alleles Associated with Ribavirin-Induced Hemolytic Anemia Among Mexican Population. Ann Hepatol 2017; 16:236-436. [PMID: 28233743 DOI: 10.5604/16652681.1231582] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prevalence of two functional polymorphisms (rs1127354 and rs7270101) of the inosine triphosphatase (ITPA) gene associated with ribavirin-induced hemolytic anemia (RIHA) during antiviral therapy for hepatitis C virus (HCV) infection varies by ethnicity. In Mexico, the distribution of these polymorphisms among Native Amerindians (NA) and admixed population (Mestizos) is unknown. This study aimed to determine the prevalence of the ITPA polymorphisms among healthy NA and Mestizos, as well as in HCV patients from West Mexico. MATERIAL AND METHODS In a cross-sectional study, 600 unrelated subjects (322 Mestizos, 100 NA, and 178 treatment-naïve, HCV-infected Mestizos patients) were enrolled. A medical history was registered. ITPA genotype was determined by Real-Time PCR. Fst-values and genetic relatedness between study and reference populations were assessed. RESULTS The frequency of the risk genotypes rs1127354CC and rs7270101AA was higher among NA (98-100%) than in Mestizos (87-92.9%), (p &lt; 0.05). The NA presented the highest prevalence of the rs1127354CC genotype reported worldwide. The Fst-values revealed a genetic relatedness among Mexican NA, South Americans and African populations (p &gt; 0.05). The frequency of the predicted risk for RIHA was higher among NA (98%) than in Mestizos (80.5%) and HCV-infected patients (81.5%) (p &lt; 0 .01). The CC/AA alleles were associated with lower values of total bilirubin, aspartate/alanine aminotransferases, and aspartate-to-platelet-ratio-index score among HCV-patients. CONCLUSION A high prevalence of the ITPA polymorphisms associated with RIHA was found in Mexican NA. These polymorphisms could be a useful tool for evaluating potential adverse effects and the risk or benefit of antiviral therapy in Mexicans and other admixed populations.
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Affiliation(s)
- Karina Gonzalez-Aldaco
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | | | - Arturo Panduro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - Erika Martinez-Lopez
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - Ketti Gleyzer
- Departamento de Patologia Clínica e Anatomia Patológica, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Nora Fierro
- Departamento de Patologia Clínica e Anatomia Patológica, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Sonia Roman
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - Norman M Kneteman
- Division of Surgery (Transplantation), University of Alberta, Edmonton, Canada
| | - Paul J Marotta
- Division of Surgery (Transplantation), University of Alberta, Edmonton, Canada
| | - Bandar Al-Judaibi
- Division of Surgery (Transplantation), University of Alberta, Edmonton, Canada
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Pharmacogénétique des immunosuppresseurs : état des connaissances et des pratiques – recommandations du Réseau national de pharmacogénétique (RNPGx). Therapie 2017; 72:269-284. [DOI: 10.1016/j.therap.2016.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/02/2016] [Indexed: 12/18/2022]
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Coppola N, De Pascalis S, Messina V, Di Caprio G, Martini S, de Stefano G, Starace M, Stornaiuolo G, Stanzione M, Ascione T, Minichini C, Sangiovanni V, Zampino R, Calò F, Rinaldi L, Persico M, Federico A, Buonomo AR, Borgia G, Gaeta GB, Filippini P, Gentile I. ITPase activity modulates the severity of anaemia in HCV-related cirrhosis treated with ribavirin-containing interferon-free regimens. Antivir Ther 2017; 22:551-558. [PMID: 28165327 DOI: 10.3851/imp3134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2017] [Indexed: 10/20/2022]
Abstract
BACKGROUND To investigate the association between inosine triphosphatase (ITPase) activity and the degree of anaemia occurring during direct-acting antiviral (DAA)/ribavirin (RBV)-based therapy in patients with cirrhosis. METHODS In a multicentre, prospective study 227 patients with HCV-related cirrhosis treated with DAA and RBV were enrolled. All patients were screened for the rs1127354 and rs7270101 ITPA single nucleotide polymorphisms using direct sequencing. RESULTS 150 (66.1%) patients had normal (100%) ITPase activity, 48 (21.1%) had moderate (60%) activity and 29 (12.8%) minimal (≤30%) activity. The ITPase activity significantly influenced the haemoglobin concentration: at day 15 it was -1.248 (sd ±0.978) in the 150 patients with an ITPase activity of 100% and -0.616 (±0.862) in the 77 patients with an ITPase activity less than 100% (P<0.000), and at day 30 it was -1.941 ±1.218 versus -1.11 ±1.218 (P<0.000). The 63 patients with a severe (at least 3/dl) haemoglobin decline, compared to those without, more frequently had an ITPase activity of 100% (82.1% versus 62.8%; P=0.021), were older (mean age ±sd: 66.7 ±8.2 versus 61.4 ±9.7 years; P=0.004) and were treated with a higher ribavirin dose (13.7 ±2.1 versus 12.8 ±2.5 mg/kg/day; P=0.008). At multivariate logistic regression analysis, the ITPase activity of 100% (OR: 2.83; 95% CI: 1.12, 7.10), male gender (OR: 3.22; 95% CI: 1.35, 7.66), body mass index (OR: 1.17; 95% CI: 1.03, 1.34) and dose of ribavirin (OR: 1.22; 95% CI: 1.06, 1.47) were independent predictors of a severe decline in haemoglobin (P<0.0001). CONCLUSIONS This study suggests that the polymorphisms in the ITPA gene influence the severity of anaemia during the first month of a DAA/RBV-based treatment in HCV-related cirrhosis.
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Affiliation(s)
- Nicola Coppola
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | | | - Giovanni Di Caprio
- Infectious Diseases Unit, AO Caserta, Caserta, Italy
- HIV Unit, Second University of Naples, Naples, Italy
| | | | - Giorgio de Stefano
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Mario Starace
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | - Gianfranca Stornaiuolo
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | - Maria Stanzione
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | - Tiziana Ascione
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Carmine Minichini
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | | | - Rosa Zampino
- Internal Medicine Unit, Department of Medical Science, Second University of Naples, Naples, Italy
| | - Federica Calò
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | - Luca Rinaldi
- Internal Medicine Unit, Department of Medical Science, Second University of Naples, Naples, Italy
| | | | | | | | | | - Giovanni Battista Gaeta
- Infectious Diseases Unit, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy
| | | | - Ivan Gentile
- Infectious Diseases Unit, University Federico II, Naples, Italy
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Woillard JB, Chouchana L, Picard N, Loriot MA. Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx). Therapie 2017; 72:285-299. [PMID: 28318610 DOI: 10.1016/j.therap.2016.09.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/02/2016] [Indexed: 12/21/2022]
Abstract
Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed.
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Affiliation(s)
- Jean-Baptiste Woillard
- Service de pharmacologie, toxicologie et pharmacovigilance, centre de biologie et de recherche en santé, CHU de Limoges, 87042 Limoges, France; Université de Limoges UMR_S850, 87000 Limoges, France.
| | - Laurent Chouchana
- Service de pharmacologie, hôpital Cochin, Assistance publique-Hôpitaux de Paris (AP-HP), 75014 Paris, France
| | - Nicolas Picard
- Service de pharmacologie, toxicologie et pharmacovigilance, centre de biologie et de recherche en santé, CHU de Limoges, 87042 Limoges, France; Université de Limoges UMR_S850, 87000 Limoges, France
| | - Marie-Anne Loriot
- Inserm UMR_S1147, centre universitaire des Saints-Pères, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Service de biochimie, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France
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Tanaka Y, Tamura Y, Yokomori H, Komiyama T. Rapidity and Severity of Hemoglobin Decreasing Associated with Erythrocyte Inosine Triphosphatase Activity and ATP Concentration during Chronic Hepatitis C Treatment. Biol Pharm Bull 2017; 39:615-9. [PMID: 27040635 DOI: 10.1248/bpb.b15-00617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of this study was to evaluate the association between therapy-induced hemoglobin (Hb) decreasing rapidity and severity with erythrocyte inosine triphosphatase (ITPase) activity and ATP concentration in chronic hepatitis C patients receiving chronic hepatitis C (HCV) treatment. Forty-three Japanese patients were included in the study. Erythrocyte ITPase activity before therapy was determined by HPLC-UV. Erythrocyte ATP concentrations before and during therapy were determined by luciferase assay. Genotyping for ITPA 94C>A (rs1127354) and IVS2+21 A>C (rs7270101) was conducted using TaqMan probes. The median ITPase activity (µmol/h/g hemoglobin) of ITPA 94 CC, CA, and AA genotypes was 136.8 (range, 80.4-289.6), 41.1 (24.3-93.1), and 11.8, respectively. ITPase activity and Hb decreasing showed a significantly inverse relationship at therapeutic weeks 2, 4, and 6 (p<0.01). Erythrocyte ATP concentration was decreased by therapy, and Hb decreasing was significantly and inversely correlated with erythrocyte ATP concentration at week 4 and after week 8 (p<0.001 and 0.05, respectively). ATP concentration for patients with ITPA 94CA was significantly lower than ITPA 94CC at week 4 (p=0.045). We concluded that ITPase activity plays an important function and that ATP concentration changes due to therapy are related to the Hb decreasing mechanism in the early period of therapy with HCV treatment.
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Affiliation(s)
- Yoichi Tanaka
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University
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Jimmerson LC, Urban TJ, Truesdale A, Baouchi-Mokrane F, Kottilil S, Meissner EG, Sims Z, Langness JA, Hodara A, Aquilante CL, Kiser JJ. Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels. J Clin Pharmacol 2017; 57:118-124. [PMID: 27349952 PMCID: PMC10725569 DOI: 10.1002/jcph.783] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/09/2016] [Indexed: 12/26/2022]
Abstract
Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/106 cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs.
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Affiliation(s)
- Leah C. Jimmerson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Thomas J. Urban
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | | | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Eric G. Meissner
- Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Zayani Sims
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Jacob A. Langness
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
- Department of Pharmacy, University of Colorado Hospital, Aurora, Colorado
| | - Ariel Hodara
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Christina L. Aquilante
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Jennifer J. Kiser
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
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Lee DK, Chang VY, Kee T, Ho CM, Ho D. Optimizing Combination Therapy for Acute Lymphoblastic Leukemia Using a Phenotypic Personalized Medicine Digital Health Platform: Retrospective Optimization Individualizes Patient Regimens to Maximize Efficacy and Safety. SLAS Technol 2016; 22:276-288. [PMID: 27920397 DOI: 10.1177/2211068216681979] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is a blood cancer that is characterized by the overproduction of lymphoblasts in the bone marrow. Treatment for pediatric ALL typically uses combination chemotherapy in phases, including a prolonged maintenance phase with oral methotrexate and 6-mercaptopurine, which often requires dose adjustment to balance side effects and efficacy. However, a major challenge confronting combination therapy for virtually every disease indication is the inability to pinpoint drug doses that are optimized for each patient, and the ability to adaptively and continuously optimize these doses to address comorbidities and other patient-specific physiological changes. To address this challenge, we developed a powerful digital health technology platform based on phenotypic personalized medicine (PPM). PPM identifies patient-specific maps that parabolically correlate drug inputs with phenotypic outputs. In a disease mechanism-independent fashion, we individualized drug ratios/dosages for two pediatric patients with standard-risk ALL in this study via PPM-mediated retrospective optimization. PPM optimization demonstrated that dynamically adjusted dosing of combination chemotherapy could enhance treatment outcomes while also substantially reducing the amount of chemotherapy administered. This may lead to more effective maintenance therapy, with the potential for shortening duration and reducing the risk of serious side effects.
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Affiliation(s)
- Dong-Keun Lee
- 1 Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA, USA
| | - Vivian Y Chang
- 2 Division of Pediatric Hematology and Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.,3 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Theodore Kee
- 4 Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA
| | - Chih-Ming Ho
- 3 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.,4 Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA.,5 Department of Mechanical and Aerospace Engineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA
| | - Dean Ho
- 1 Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA, USA.,3 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.,4 Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA.,6 Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.,7 California NanoSystems Institute, UCLA, Los Angeles, CA, USA
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50
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Peltenburg NC, Leers MPG, Bakker JA, Lowe SH, Vroemen WHM, Paulussen ADC, van den Bosch BJC, Bierau J, Verbon A. Inosine Triphosphate Pyrophosphohydrolase Expression: Decreased in Leukocytes of HIV-Infected Patients Using Combination Antiretroviral Therapy. J Acquir Immune Defic Syndr 2016; 73:390-395. [PMID: 27792682 DOI: 10.1097/qai.0000000000001130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE In HIV-infected patients, the enzyme Inosine triphosphate pyrophosphohydrolase (ITPase), involved in purine nucleotide homeostasis, was found to be decreased in erythrocytes. Since purine analogues are pivotal in the HIV treatment, a better understanding of ITPase expression in CD4 lymphocytes may lead to better understanding of nucleotide metabolism and (adverse) effects. DESIGN Cross-sectional, cohort, observational study. METHODS HIV-infected and control patients above 18 years were included. All DNA samples were genotyped for the 2 functional ITPA SNPs; c.94C>A (rs1127354) and g.IVS+21A>C (rs7270101). ITPase expression was determined by flow cytometry in all leukocyte subsets. RESULTS Fifty-nine HIV-infected patients and 50 controls were included. Leukocyte subtype distribution showed no difference in monocytes and granulocytes, but lymphocytes were higher in HIV-infected patients (P < 0.001). ITPase expression was highest in activated monocytes and lowest in lymphocytes. In HIV-infected patients, the percentage of ITPase positive cells was less in all leukocyte and lymphocyte subsets compared with controls (P < 0.01). In HIV-infected patients, 97.4% of CD4 lymphocytes were ITPase positive versus 99.9% in controls (P = 0.002) and 85.9% versus 99.6% of CD8 lymphocytes (P < 0.0001), respectively. Stratification according to genotype revealed no significant differences in ITPase expression in leukocytes in HIV-infected and control patients. CONCLUSIONS HIV-infection seems to be interfering with the nucleotide metabolism in leukocytes, including CD4 lymphocytes, by decreasing ITPase expression, independently of ITPA genotype. Given that active metabolites of purine-analogue reverse transcriptase inhibitors are potential substrates for ITPase, these results warrant further research towards effectiveness and adverse events of purine analogues and ITPase activity.
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Affiliation(s)
- N Chantal Peltenburg
- *Department of Internal Medicine, Division of Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands;†Department of Clinical Chemistry and Hematology, Zuyderland Medical Center, Heerlen, the Netherlands;‡Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands;Departments of §Medical Microbiology;‖Internal Medicine, Division of Infectious Diseases, Research School CAPHRI, Maastricht University Medical Center, Maastricht, the Netherlands;¶Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands; and#Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands
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