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Dobritzsch D, Meijer J, Meinsma R, Maurer D, Monavari AA, Gummesson A, Reims A, Cayuela JA, Kuklina N, Benoist JF, Perrin L, Assmann B, Hoffmann GF, Bierau J, Kaindl AM, van Kuilenburg ABP. β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity. Mol Genet Metab 2022; 136:177-185. [PMID: 35151535 DOI: 10.1016/j.ymgme.2022.01.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 01/04/2023]
Abstract
β-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid to β-alanine and β-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete β-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified β-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid in urine. Analysis of UPB1, encoding β-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant ß-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased β-ureidopropionase activity. Analysis of the crystal structure of human ß-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional β-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish β-ureidopropionase patients, indicating that β-ureidopropionase deficiency may be more common than anticipated.
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Affiliation(s)
- Doreen Dobritzsch
- Uppsala University, Department of Chemistry-BMC, Biomedical Center, Uppsala, Sweden
| | - Judith Meijer
- Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam, the Netherlands
| | - Rutger Meinsma
- Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam, the Netherlands
| | | | - Ardeshir A Monavari
- National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street, Temple Street, Dublin, Ireland
| | - Anders Gummesson
- Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Gothenburg, Sweden
| | - Annika Reims
- Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Jorge A Cayuela
- Sahlgrenska University Hospital, Department of Clinical Genetics and Genomics, Gothenburg, Sweden
| | - Natalia Kuklina
- Drammen Hospital, Pediatric Department/Habilitation Center, Vestre Viken HF, Drammen, Norway
| | - Jean-François Benoist
- Hôpital Universitaire Robert Debré, Service de Biochimie Hormonologie, Paris, France
| | - Laurence Perrin
- Hôpital Universitaire Robert Debré, Service de Biochimie Hormonologie, Paris, France
| | - Birgit Assmann
- University Children's Hospital, University of Heidelberg, Heidelberg, Germany
| | - Georg F Hoffmann
- University Children's Hospital, University of Heidelberg, Heidelberg, Germany
| | - Jörgen Bierau
- Maastricht University Medical Centre, Department of Clinical Genetics, Maastricht, the Netherlands; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands
| | - Angela M Kaindl
- Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Center for Chronically Sick Children, Institute for Cell and Neurobiology, Berlin, Germany
| | - André B P van Kuilenburg
- Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam, the Netherlands.
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Xu X, Zheng J, Zou Q, Wang C, Zhang X, Wang X, Liu Y, Shu J. Rapid screening of UPB1 gene variations by high resolution melting curve analysis. Exp Ther Med 2021; 21:403. [PMID: 33692834 PMCID: PMC7938451 DOI: 10.3892/etm.2021.9834] [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: 02/12/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to analyze gene mutations in patients with β-ureidopropinoase deficiency and establish a rapid detection method for β-ureidopropinoase (UPB1) pathogenic variations by high resolution melting (HRM) analysis. DNA samples with known UPB1 mutations in three patients with β-ureidopropinoase deficiency were utilized to establish a rapid detection method for UPB1 pathogenic variations by HRM analysis. Further rapid screening was performed on two patients diagnosed with β-ureidopropinoase deficiency and 50 healthy control individuals. The results showed that all known UPB1 gene mutations can be analyzed by a specially designed HRM assay. Each mutation has specific HRM profiles which could be used in rapid screening. The HRM method could correctly identify all genetic mutations in two children with β-ureidopropinoase deficiency. In addition, the HRM assay also recognized four unknown mutations. To conclude, the results support future studies of applying HRM analysis as a diagnostic approach for β-ureidopropinoase deficiency and a rapid screening method for UPB1 mutation carriers.
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Affiliation(s)
- Xiaowei Xu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin 300134, P.R. China.,Tianjin Key Laboratory of Prevention and Treatment of Birth Defects, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Jie Zheng
- Graduate College, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Qianqian Zou
- Graduate College, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Chao Wang
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin 300134, P.R. China.,Tianjin Key Laboratory of Prevention and Treatment of Birth Defects, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Xinjie Zhang
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin 300134, P.R. China.,Tianjin Key Laboratory of Prevention and Treatment of Birth Defects, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Xuetao Wang
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin 300134, P.R. China.,Tianjin Key Laboratory of Prevention and Treatment of Birth Defects, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Yang Liu
- Department of Neonatology, Tianjin Children's Hospital, Tianjin 300134, P.R. China
| | - Jianbo Shu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin 300134, P.R. China.,Tianjin Key Laboratory of Prevention and Treatment of Birth Defects, Tianjin Children's Hospital, Tianjin 300134, P.R. China
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Deac AL, Burz CC, Bocşe HF, Bocşan IC, Buzoianu AD. A review on the importance of genotyping and phenotyping in fluoropyrimidine treatment. Med Pharm Rep 2020; 93:223-230. [PMID: 32832886 PMCID: PMC7418836 DOI: 10.15386/mpr-1564] [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] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/24/2020] [Accepted: 03/20/2019] [Indexed: 12/23/2022] Open
Abstract
Fluoropyrimidines, after more than 50 years from their discovery, are still the treatment of many types of cancer, and it is estimated that two million patients receive fluoropyrimidine therapy annually. The toxicity associated with fluoropyrimidines affects 30–40% of patients and some adverse effects can be lethal. Dihydroypyrimidine dehydrogenase is the main enzyme in the catabolism of 5-FU and DPD activity deficiency can cause important toxicity. This is an important reason to determine DPD activity in order to improve patient safety and to limit potential life-threating toxicity. At presentmultiple phenotypic and genotypic methods are available for the determination of DPD activity, some of these methods have proven their usefulness in practice, and yet they are not routinely recommended in clinical practice. This review is another statement of the importance of the determination of DPD status, the phenotypic and genotypic methods that are available and can be used.
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Affiliation(s)
| | - Claudia Cristina Burz
- "Prof. Dr. Ion Chiricuţă" Oncology Institute, Cluj-Napoca, Romania.,Immunology and Allergology, Department 2 - Functional Sciences, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Horea Florin Bocşe
- "Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 3 General Surgery Clinic, Cluj-Napoca, Romania
| | - Ioana Corina Bocşan
- Pharmacology, Toxicology and Clinical Pharmacology, Department 2 - Functional Biosciences, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Anca-Dana Buzoianu
- Pharmacology, Toxicology and Clinical Pharmacology, Department 2 - Functional Biosciences, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase. J Clin Med 2020; 9:jcm9082342. [PMID: 32707991 PMCID: PMC7464968 DOI: 10.3390/jcm9082342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/21/2020] [Accepted: 07/21/2020] [Indexed: 01/22/2023] Open
Abstract
Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.
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Cunha-Junior GF, Bastos-Rodrigues L, Azevedo PG, Bicalho MA, Magno LAV, De Marco L, Coelho LG. Prevalence of the DPYD variant (Y186C) in Brazilian individuals of African ancestry. Cancer Chemother Pharmacol 2019; 84:1359-1363. [PMID: 31641844 DOI: 10.1007/s00280-019-03974-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/05/2019] [Indexed: 10/25/2022]
Abstract
PURPOSE The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians. METHODS We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry. RESULTS The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%. CONCLUSIONS The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.
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Affiliation(s)
- Geraldo Felício Cunha-Junior
- Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Department of Oncology, Hospital da Baleia, Fundação Benjamim Guimarães, Belo Horizonte, Brazil
| | - Luciana Bastos-Rodrigues
- Department of Nutrition, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Molecular Medicine Technology Center, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Pedro G Azevedo
- Molecular Medicine Technology Center, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maria Aparecida Bicalho
- Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Molecular Medicine Technology Center, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiz Alexandre V Magno
- Molecular Medicine Technology Center, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiz De Marco
- Department of Surgery, Federal University of Minas Gerais, Av. Professor Alfredo Balena 190, Belo Horizonte, 30130-100, Brazil.
- Molecular Medicine Technology Center, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
| | - Luiz Gonzaga Coelho
- Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Preliminary Evidence for Enhanced Thymine Absorption: A Putative New Phenotype Associated With Fluoropyrimidine Toxicity in Cancer Patients. Ther Drug Monit 2018; 40:495-502. [PMID: 29846282 DOI: 10.1097/ftd.0000000000000532] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Thus, the cause of most fluorouracil toxicity cases remains unexplained. METHODS For this small cohort study, thymine (THY) 250 mg was administered orally to 6 patients who had experienced severe toxicity during treatment with 5FU or capecitabine. Plasma and urine were analyzed for THY and its catabolites dihydrothymine (DHT) and β-ureidoisobutyrate. RESULTS Of the 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSIONS This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted.
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Chavani O, Jensen BP, Strother RM, Florkowski CM, George PM. Development, validation and application of a novel liquid chromatography tandem mass spectrometry assay measuring uracil, 5,6-dihydrouracil, 5-fluorouracil, 5,6-dihydro-5-fluorouracil, α-fluoro-β-ureidopropionic acid and α-fluoro-β-alanine in human plasma. J Pharm Biomed Anal 2017; 142:125-135. [DOI: 10.1016/j.jpba.2017.04.055] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 04/23/2017] [Accepted: 04/24/2017] [Indexed: 12/27/2022]
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Abstract
Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.
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Affiliation(s)
| | | | - André B P van Kuilenburg
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, F0-220, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Meulendijks D, Cats A, Beijnen JH, Schellens JHM. Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity - Ready for clinical practice? Cancer Treat Rev 2016; 50:23-34. [PMID: 27589829 DOI: 10.1016/j.ctrv.2016.08.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/04/2016] [Accepted: 08/08/2016] [Indexed: 01/05/2023]
Abstract
Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Activity of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD), is the key determinant of 5-FU pharmacology, and accounts for around 80% of 5-FU catabolism. There is a consistent relationship between DPD activity and 5-FU exposure on the one hand, and risk of severe and potentially lethal fluoropyrimidine-associated toxicity on the other hand. Therefore, there is a sound rationale for individualizing treatment with fluoropyrimidines based on DPD status in order to improve patient safety. The field of individualized treatment with fluoropyrimidines is now rapidly developing. The main strategies that are available, are based on genotyping of the gene encoding DPD (DPYD) and measuring of pretreatment DPD phenotype. Clinical validity of additional approaches, including genotyping of MIR27A has also recently been demonstrated. Here, we critically review the evidence on clinical validity and utility of strategies available to clinicians to identify patients at risk of developing severe and potentially fatal toxicity as a result of DPD deficiency. We evaluate the advantages and limitations of these methods when used in clinical practice, and discuss for which strategies clinical implementation is currently justified based on the available evidence and, in addition, which additional data will be required before implementing other, as yet less developed strategies.
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Affiliation(s)
- Didier Meulendijks
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands.
| | - Annemieke Cats
- Department of Gastroenterology & Hepatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jan H M Schellens
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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Kummer D, Froehlich TK, Joerger M, Aebi S, Sistonen J, Amstutz U, Largiadèr CR. Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity. Pharmacogenomics 2015; 16:1367-77. [DOI: 10.2217/pgs.15.81] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aims: To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy. Patients & methods: The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients. Results & conclusions: Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1–1T > C: padjusted = 0.003; OR = 2.53; 95% CI: 1.39–4.62, and c.265–58T > C: padjusted = 0.039; OR = 0.61; 95% CI: 0.38–0.97) with 5-fluorouracil toxicity were replicated.
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Affiliation(s)
- Dominic Kummer
- Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland
- Graduate School for Cellular & Biomedical Sciences, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland
| | - Tanja K Froehlich
- Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland
| | - Markus Joerger
- Department of Medical Oncology & Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland
| | - Stefan Aebi
- Division of Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, CH-6000 Lucerne 16, Switzerland
| | - Johanna Sistonen
- Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland
| | - Ursula Amstutz
- Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland
| | - Carlo R Largiadèr
- Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland
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Shu J, Lv X, Jiang S, Zhang Y, Zhang C, Meng Y, Situ A, Xu H, Song L. Genetic analysis of the UPB1 gene in two new Chinese families with β-ureidopropionase deficiency and the carrier frequency of the mutation c.977G>A in Northern China. Childs Nerv Syst 2014; 30:2109-14. [PMID: 25236466 DOI: 10.1007/s00381-014-2541-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 08/26/2014] [Indexed: 12/27/2022]
Abstract
PURPOSE The purpose of the study was to investigate mutations of the UPB1 gene in two Chinese families with β-ureidopropionase deficiency and the heterozygous carrier frequency in Chinese. METHODS Genomic DNA was extracted from peripheral blood leukocytes from all available family members and 500 unrelated healthy controls. Then, all exons and flanking intron regions of the UPB1 gene were amplified by PCR and analyzed by direct sequencing in two patient-families. Finally, the carrier frequency of the c.977G>A (p.R326Q) mutation was identified by PCR restriction fragment length polymorphism in 500 healthy controls. RESULTS The two patients had the same homozygous missense mutation in exon 9 (c.977G>A; p.R326Q), and the carrier frequency of this mutation was 2.8 % in the Northern Chinese population, which suggests that about 1:5,102 Chinese are expected to suffer from UPB1 deficiency. CONCLUSIONS The c.977G>A (p.R326Q) is the most common mutation of the UPB1 gene in Chinese. The predicted incidence indicates that β-ureidopropionase deficiency is significantly underdiagnosed in the Chinese population. It should be necessary to add β-ureidopropionase deficiency to high-risk screening for the symptomatic patients group.
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Affiliation(s)
- Jianbo Shu
- Tianjin Pediatric Research Institute, Tianjin Children's Hospital, Tianjin, China
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Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NGGM, Roelofsen J, Zoetekouw L, Watanabe Y, Tashiro K, Lee T, Takeshima Y, Mitsubuchi H, Yoneyama A, Ohta K, Eto K, Saito K, Kuhara T, van Kuilenburg ABP. Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected]. J Inherit Metab Dis 2014; 37:801-12. [PMID: 24526388 PMCID: PMC4158181 DOI: 10.1007/s10545-014-9682-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 01/18/2014] [Accepted: 01/21/2014] [Indexed: 11/13/2022]
Abstract
β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.
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Affiliation(s)
- Yoko Nakajima
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands,
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Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis 2014; 37:687-98. [PMID: 25030255 DOI: 10.1007/s10545-014-9742-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 06/05/2014] [Accepted: 06/24/2014] [Indexed: 10/25/2022]
Abstract
Inborn errors involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into their fundamental physiological roles as vital constituents of nucleic acids as well as substrates of lipid and carbohydrate metabolism and in oxidative phosphorylation. Genetic aberrations of pyrimidine pathways lead to diverse clinical manifestations including neurological, immunological, haematological, renal impairments, adverse reactions to analogue therapy and association with malignancies. Maintenance of cellular nucleotides depends on the three aspects of metabolism of pyrimidines: de novo synthesis, catabolism and recycling of these metabolites. Of the ten recognised disorders of pyrimidine metabolism treatment is currently restricted to only two disorders: hereditary orotic aciduria (oral uridine therapy) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; allogeneic hematopoetic stem cell transplant and enzyme replacement). The ubiquitous role that pyrimidine metabolism plays in human life highlights the importance of improving diagnostic evaluation in suggestive clinical settings, which will contribute to the elucidation of new defects, future development of novel drugs and therapeutic strategies. Limited awareness of the expanding phenotypic spectrum, with relatively recent descriptions of newer disorders, compounded by considerable genetic heterogeneity has often contributed to the delays in the diagnosis of this group of disorders. The lack of an easily recognisable, easily measurable end product, akin to uric acid in purine metabolism, has contributed to the under-recognition of these disorders.This review describes the currently known inborn errors of pyrimidine metabolism, their variable phenotypic presentations, established diagnostic methodology and recognised treatment options.
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Affiliation(s)
- Shanti Balasubramaniam
- Metabolic Unit, Princess Margaret Hospital, Roberts Road, Subiaco, Perth, WA, 6008, Australia
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Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 2014; 20:9775-827. [PMID: 25110414 PMCID: PMC4123365 DOI: 10.3748/wjg.v20.i29.9775] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/17/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
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13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients. Cancer Chemother Pharmacol 2013; 72:1273-82. [DOI: 10.1007/s00280-013-2309-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 09/25/2013] [Indexed: 11/26/2022]
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Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol 2012; 3:251-61. [PMID: 22943016 DOI: 10.3978/j.issn.2078-6891.2012.021] [Citation(s) in RCA: 236] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 04/05/2012] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer remains one of the deadly diseases with poor prognosis. New classification of gastric cancers based on histologic features, genotypes and molecular phenotypes helps better understand the characteristics of each subtype, and improve early diagnosis, prevention and treatment. The objective of this article is to review the new classification of gastric cancers and the up-to-date guidance in the application of molecular testing.
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Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity. Pharmacol Rep 2012; 64:1234-42. [DOI: 10.1016/s1734-1140(12)70919-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Revised: 05/11/2012] [Indexed: 11/18/2022]
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A rapid HPLC-ESI-MS/MS method for determination of dihydrouracil/uracil ratio in plasma: evaluation of toxicity to 5-flurouracil in patients with gastrointestinal cancer. Ther Drug Monit 2012; 34:59-66. [PMID: 22210098 DOI: 10.1097/ftd.0b013e318240405f] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND A liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of endogenous uracil (U) and dihydrouracil (UH2) was developed and tested in a Brazilian population of patients with gastrointestinal cancer previously exposed to 5-fluorouracil (5FU). METHODS The analytes were extracted by a liquid-liquid method using 5-clorouracil as internal standard. The separation was performed on a reversed-phase XTerra C18 column with a mobile phase composed of methanol and aqueous 0.1% ammonium hydroxide (15:85). Mass spectrometry detection was carried out using negative electrospray ionization and selected reaction monitoring. Bovine serum albumin was employed as an alternative matrix to prepare the calibration standards, aiming to avoid the measurement of physiologic U and UH2. Calibration curves were constructed over the range of 5-200 ng/mL for U and 10-500 ng/mL for UH2. RESULTS The mean RSD values in the intrarun precision were 6.5% and 10.0% and in the interrun precision were 7.8% and 9.0% for U and UH2, respectively. The mean accuracy values were within the range of 90%-110% for both analytes. The analytes were stable in plasma under different conditions of temperature and time. The validated method was successfully applied to determine the plasma concentrations of U and UH2 in patients with gastrointestinal cancer (n = 32) previously treated with 5FU and for whom clinical toxicity was well documented. U concentrations varied from 21.8 to 56.6 ng/mL, whereas UH2 concentrations varied from 57.7 to 271.5 ng/mL. UH2/U ratio ranged from 1.56 to 6.18. CONCLUSIONS The method has proved to provide a quick, reliable, and reproducible quantitation of the plasma concentrations of U and its metabolite UH2. The UH2/U ratios did not discriminate patients previously exposed to 5FU with and without severe toxicities, possibly due to the small sample. Further studies in a larger population are desirable.
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van Kuilenburg ABP, Dobritzsch D, Meijer J, Krumpel M, Selim LA, Rashed MS, Assmann B, Meinsma R, Lohkamp B, Ito T, Abeling NGGM, Saito K, Eto K, Smitka M, Engvall M, Zhang C, Xu W, Zoetekouw L, Hennekam RCM. ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1096-108. [PMID: 22525402 DOI: 10.1016/j.bbadis.2012.04.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 03/29/2012] [Accepted: 04/09/2012] [Indexed: 12/26/2022]
Abstract
ß-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.
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Affiliation(s)
- André B P van Kuilenburg
- Academic Medical Center, Emma Children's Hospital, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, 1105 AZ Amsterdam, The Netherlands.
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Wettergren Y, Carlsson G, Odin E, Gustavsson B. Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5-fluorouracil-based chemotherapy. Cancer 2011; 118:2935-43. [PMID: 22020693 DOI: 10.1002/cncr.26595] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Revised: 08/15/2011] [Accepted: 09/07/2011] [Indexed: 01/04/2023]
Abstract
BACKGROUND In Nordic countries, the standard treatment of colorectal cancer (CRC) in the adjuvant setting is bolus 5-fluorouracil (5-FU) plus leucovorin alone or in combination with oxaliplatin. 5-FU competes with the natural occurring pyrimidine uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD; enzyme commission number 1.3.1.2). Low DPD activity is associated with toxicity during treatment. Pretherapeutic detection of DPD deficiency could prevent severe toxicity otherwise limiting drug administration. Assays showing that DPD deficiency impairs breakdown of Ura to dihydrouracil (UH(2)) seem promising for clinical use. METHODS Urine was collected from 56 untreated volunteers and 143 patients with CRC before adjuvant treatment. Ura and UH(2) were analyzed using a column-switching high-performance liquid chromatography method that incorporates reversed-phase and cation-exchange columns. Ura, UH(2), and UH(2)/Ura levels were related to toxicity. RESULTS Ura and UH(2) in patients were not different from controls. UH(2) was significantly higher in women compared with men. The UH(2)/Ura ratio, however, did not differ according to sex. Low UH(2) and UH(2)/Ura levels were associated with diarrhea in men. Women experiencing thrombocytopenia had significantly higher Ura compared with women with no thrombocytopenia. The UH(2)/Ura ratio correlated negatively with total toxicity score in men (r = -0.39, P = .020). CONCLUSION Pretherapeutic Ura and UH(2) levels per se may be related to risk of side effects during adjuvant 5-FU-based treatment, whereas the UH(2)/Ura ratio may not always reveal such a risk. Sex is a strong risk factor for toxicity, showing the importance of evaluating male and female patients separately.
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Affiliation(s)
- Yvonne Wettergren
- Surgical-Oncology Laboratory, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, the Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
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Muhale FA, Wetmore BA, Thomas RS, McLeod HL. Systems pharmacology assessment of the 5-fluorouracil pathway. Pharmacogenomics 2011; 12:341-50. [PMID: 21449674 DOI: 10.2217/pgs.10.188] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIM To assess the impact of the 5-fluorouracil (5-FU) drug-pathway genes on cytotoxicity, and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes. MATERIALS & METHODS Dose-response experiments were used to quantify the phenotype of sensitivity to 5-FU following the specific knockdown of genes selected from the 5-FU PharmGKB drug pathway in three human colorectal cell lines. Changes in sensitivity were considered significant if the IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells. RESULTS Of the 24 genes analyzed, 13 produced significant changes on the phenotype of sensitivity to 5-FU (DHFR, DPYS, DTYMK, DUT, FPGS, GGH, NME1, NT5C, RRM1, TYMS, UCK2, UNG and UMPS). CONCLUSION The RNAi screening strategy enabled prioritization of the genes from the 5-FU drug pathway. Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples.
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Affiliation(s)
- Filipe A Muhale
- UNC Institute for Pharmacogenomics & Individualized Therapy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7361, USA
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Ciccolini J, Gross E, Dahan L, Lacarelle B, Mercier C. Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Clin Colorectal Cancer 2011; 9:224-8. [PMID: 20920994 DOI: 10.3816/ccc.2010.n.033] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
5-Fluorouracil (5-FU) is a mainstay for treating colorectal cancer, alone or more frequently as part of combination therapies. However, its efficacy/toxicity balance is often limited by the occurrence of severe toxicities, showing in about 15%-20% of patients. Several clinical reports have shown the deleterious effect of dihydropyrimidine dehydrogenase (DPD) genetic polymorphism, a condition that reduces the liver detoxification step of standard dosages of 5-FU, in patients undergoing fluoropyrimidine-based therapy. Admittedly, DPD deficiency accounts for 50%-75% of the severe and sometimes life-threatening toxicities associated with 5-FU (or oral 5-FU). However, technical consensus on the best way to identify patients with DPD deficiency before administrating 5-FU is far from being achieved. Consequently, no regulatory step has been undertaken yet to recommend DPD testing as part of routine clinical practice for securing the administration of 5-FU. This review covers the limits and achievements of the various strategies proposed so far for determining DPD status in patients scheduled for 5-FU therapy.
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Rangwala HS, Giraldes JW, Gurvich VJ. Synthesis and purification of [2-13C]-5-fluorouracil. J Labelled Comp Radiopharm 2011. [DOI: 10.1002/jlcr.1872] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Ezzeldin HH, Acosta EP, Mattison LK, Fourie J, Modak A, Diasio RB. (13)C-5-FU breath test current status and future directions: a comprehensive review. J Breath Res 2009; 3:047002. [PMID: 21386199 DOI: 10.1088/1752-7155/3/4/047002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Breath tests (BTs) represent a safe non-invasive alternative strategy that could provide valuable diagnostic information in conditions like fat malabsorption, carbohydrate (lactose and fructose) malabsorption, liver dysfunction, impaired gastric emptying, abnormal small bowel transit time, small intestinal bacterial overgrowth and Helicobacter pylori infection. To date, despite the availability of a number of breath tests, only three have gained approval by the FDA for application in a clinical setting ((13)C-urea breath test for the detection of H. pylori; NO breath test for monitoring asthma and alkane breath test for heart transplant rejection). Unfortunately, none of these tests investigate cancer patients or response to cancer chemotherapy. Several years ago it was realized that the presence of a reliable non-invasive approach could assist in the detection of patients at risk of developing severe life-threatening toxicities prior to the administration of fluoropyrimidines (e.g. 5-FU) or related cancer chemotherapy. 5-FU toxicity results mainly from deficient uracil catabolism. This review discusses the development of a BT that utilizes an orally administered pyrimidine ([2-(13)C]-uracil) which is metabolized via the same catabolic pathway as 5-FU. This ([2-(13)C]-uracil) breath test could provide a valuable addition to the patients' standard of care.
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Affiliation(s)
- Hany H Ezzeldin
- Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
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