DOCSLIB.ORG

Is TPMT Testing a Predictor of Duration of Use Or Long-Term Benefit of Thiopurine Agents? Shatoya R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Is TPMT Testing a Predictor of Duration of Use Or Long-Term Benefit of Thiopurine Agents? Shatoya R Grand Valley State University ScholarWorks@GVSU Masters Theses Graduate Research and Creative Practice 12-2018 Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya R. Wilson Grand Valley State University Follow this and additional works at: https://scholarworks.gvsu.edu/theses Part of the Chemical and Pharmacologic Phenomena Commons Recommended Citation Wilson, Shatoya R., "Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents?" (2018). Masters Theses. 914. https://scholarworks.gvsu.edu/theses/914 This Thesis is brought to you for free and open access by the Graduate Research and Creative Practice at ScholarWorks@GVSU. It has been accepted for inclusion in Masters Theses by an authorized administrator of ScholarWorks@GVSU. For more information, please contact [email protected]. Is TPMT Testing a Predictor of Duration of Use or Long-Term Benefit of Thiopurine Agents? Shatoya Renee Wilson A Thesis Submitted to the Graduate Faculty of GRAND VALLEY STATE UNIVERSITY In Partial Fulfillment of the Requirements For the Degree of Master of Health Science Biomedical Science December 2018 Dedication This is dedicated to my sister and father, for their support and love. I thank you for listening to me when I needed to practice with or vent to someone. I would also like to dedicate this to my thesis committee, who helped me grow as a student and researcher. For your guidance, I am grateful. 3 Acknowledgements I would like to thank my thesis committee, Dr. Debra Burg, David Chesla, and Dr. John Capodilupo for their mentorship and guidance. I would also like to thank the Spectrum Health Department of Research for providing the research database from which my study was obtained. Special thanks to Spectrum Health biostatisticians Brandon George and Jessica Parker for their statistical consulting. 4 Abstract Background Inflammatory Bowel Disease (IBD) affects as many as 1.3 million Americans and includes both ulcerative colitis (UC) and Crohn’s disease (CD). Recent practices have moved towards using immunomodulators early in the course of disease to prevent disease progression. Patients have shown improved outcomes on immunomodulators compared to aminosalicylates, and reduced risk for tachyphylaxis compared to corticosteroid treatment. Thiopurine agents such as azathioprine and 6-mercaptopurine are immunomodulators often used to treat IBD. Unfortunately, many patients experience cytotoxicity from thiopurine use. Recent studies have shown that patients deficient in thiopurine-S-methyltransferase (TMPT), produce an overabundance of the therapeutic end product, 6-thioguanine nucleotide (6-TGN), causing toxicity leading to apoptosis in all types of immune cells. In this study we investigated whether pre-emptive genotyping for TPMT would allow customized doses of thiopurines based on TPMT status and whether knowing this genotyping would reduce the risk of adverse events without compromising disease control. Methods A retrospective study using an available data set identified 30 adults over 18 with CD or UC. Patients were included in the study if their TPMT genotype and phenotype, 6-TGN and 6- MeMPN levels, and disease exacerbation were recorded. Using Fisher’s Exact test for statistical analysis, genotype was compared to phenotype (enzyme activity), metabolite levels, and toxicity/exacerbation. Phenotype was compared to metabolite levels. Results Genotype and enzymatic activity were not independent of each other. Subjects with a mutant TPMT genotype were more likely to respond to thiopurine therapies. Genotype was not 5 indicative of high risk for hepatotoxicity, and there was no significant relationship between enzyme activity and metabolite levels. Lastly, there was no relationship between genotype and toxicity. Conclusions Multiple studies have studied dose escalation based on genotype alone. However, genotype does not take into consideration confounding factors that might impact patient outcomes when using thiopurine therapy for IBD. This would include rare deficiency alleles, true phenotypic expression, other genetic polymorphisms, and most importantly polypharmacy. Thiopurine interaction with ASAs, benzoic acid derivatives, non-steroidal anti-inflammatory drugs, and methotrexate have been shown to influence TPMT enzyme activity. Whether this is due to allosteric inhibition or competitive inhibition has yet to be discovered. 6 Table of Contents Dedication .................................................................................................................................. 3 Acknowledgements ................................................................................................................... 4 Abstract ..................................................................................................................................... 5 Table of Contents ...................................................................................................................... 7 List of Tables ............................................................................................................................. 8 List of Figures ........................................................................................................................... 9 Chapter 1 Introduction ............................................................................................................ 10 Introduction .................................................................................................................... 10 Purpose ........................................................................................................................... 13 Significance .................................................................................................................... 14 Chapter 2 Review of Literature .............................................................................................. 15 Characteristics of IBD .................................................................................................... 15 Metabolomics of thiopurines .......................................................................................... 18 Achieving a therapeutic response ................................................................................... 20 Balance between efficacy and toxicity ........................................................................... 21 Genetic polymorphism ................................................................................................... 21 Polypharmacy drug interactions and TPMT activity ...................................................... 23 Conclusion ...................................................................................................................... 29 Chapter 3 Methodology ........................................................................................................... 30 Experimental Design ...................................................................................................... 30 Definitions ...................................................................................................................... 30 Subjects ........................................................................................................................... 30 Data Collection ............................................................................................................... 31 Statistical Analysis ......................................................................................................... 32 Chapter 4 Results ..................................................................................................................... 33 Genotype vs. Phenotype ................................................................................................. 33 Metabolite Levels ........................................................................................................... 34 Genotype vs. Cytotoxicity .............................................................................................. 37 Chapter 5 Discussion and Conclusions ................................................................................... 39 References ................................................................................................................................. 44 7 List of Tables Table 1. ....................................................................................................................................... 31 Criteria for diagnosing CD and UC. Table 2. ....................................................................................................................................... 33 Demographics compared between groups, N=30. Table 3. ....................................................................................................................................... 34 TPMT genotype versus TPMT enzyme activity, N=30. Table 4. ....................................................................................................................................... 35 Genotype vs. responsiveness to 6-TGN therapy, N=17. Table 5. ....................................................................................................................................... 36 Genotype vs. risk of hepatotoxicity with 6-MeMPN levels, N=17. Table 6. ....................................................................................................................................... 37 Phenotype vs. responsiveness
Load more

Recommended publications
  • Thiopurine Drug Therapy
    Thiopurine Drug Therapy Thiopurine drug therapy is used for autoimmune diseases, inflammatory bowel disease, acute lymphoblastic leukemia, and to prevent rejection after solid organ transplant. The inactivation of thiopurine drugs is catalyzed in part by thiopurine Tests to Consider methyltrasferase (TPMT) and nudix hydrolase 15 (NUDT15). Variants in the TPMT and/or NUDT15 genes are associated with an accumulation of cytotoxic metabolites Thiopurine Methyltransferase, RBC leading to increased risk of drug-related toxicity with standard doses of thiopurine 0092066 drugs, and the effects on thiopurine catabolism can be additive. Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry The enzyme activity phenotype of TPMT can also be measured directly when Phenotype test to assess risk for severe performed prior to drug administration. Complementary to pretherapeutic tests, myelosuppression with standard dosing of concentrations of thiopurines and metabolites can be measured after initiation of thiopurine drugs therapy to optimize dose. Use for individuals being considered for thiopurine therapy Must be performed before thiopurine therapy is initiated Disease Overview Can also detect rapid metabolizer phenotype Prevalence TPMT and NUDT15 3001535 Method: Polymerase Chain Very low/absent TPMT activity: ~3/1,000 individuals Reaction/Fluorescence Monitoring Intermediate TPMT activity: ~10% of Caucasian individuals Normal TPMT activity: ~90% of individuals Genotyping test to assess genetic risk for severe myelosuppression
    [Show full text]
  • Identification and Analysis of Single-Nucleotide Polymorphisms in the Gemcitabine Pharmacologic Pathway
    The Pharmacogenomics Journal (2004) 4, 307–314 & 2004 Nature Publishing Group All rights reserved 1470-269X/04 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway AK Fukunaga1 ABSTRACT 2 Significant variability in the antitumor efficacy and systemic toxicity of S Marsh gemcitabine has been observed in cancer patients. However, there are 1 DJ Murry currently no tools for prospective identification of patients at risk for TD Hurley3 untoward events. This study has identified and validated single-nucleotide HL McLeod2 polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes 1Department of Clinical Pharmacy and Pharmacy involved in gemcitabine metabolism. Pyrosequencing was utilized to Practice, Purdue University, W. Lafayette, IN, determine the SNP allele frequencies in genomic DNA from European and 2 USA; Departments of Medicine, Genetics, and African populations (n ¼ 190). A total of 14 genetic variants (including 12 Molecular Biology and Pharmacology, Washington University School of Medicine and SNPs) were identified in eight of the gemcitabine metabolic pathway genes. the Siteman Cancer Center, St Louis, MO, USA; The majority of the database variants were observed in population samples. 3Department of Biochemistry and Molecular Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that Biology, Indiana University School of Medicine, were found to be significantly different between the European and African Indianapolis, IN, USA populations (Po0.05). This study provides the first step to identify markers Correspondence: for predicting variability in gemcitabine response and toxicity. Dr HL McLeod, Washington University The Pharmacogenomics Journal (2004) 4, 307–314.
    [Show full text]
  • Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 May 2019 doi:10.20944/preprints201905.0358.v1 Peer-reviewed version available at Int. J. Mol. Sci. 2019, 20, 3210; doi:10.3390/ijms20133210 1 of 39 1 Review 2 Recent topics on the mechanisms of 3 immunosuppressive therapy-related neurotoxicities 4 Wei Zhang 1, Nobuaki Egashira 1,2,* and Satohiro Masuda 1,2 5 1 Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, 6 Kyushu University, Fukuoka 812-8582, Japan 7 2 Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan 8 * Correspondence: [email protected], Tel.: 81-92-642-5920 9 Abstract: Although transplantation procedures have been developed for patients with end-stagec 10 hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. 11 Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin 12 inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly 13 increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is 14 commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. 15 The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability 16 or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in 17 electrophysiological state. Other immunosuppressants can also induce neuropsychiatric 18 complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces 19 depression and headache; methotrexate affects the central nervous system; mouse monoclonal 20 immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and 21 patients using corticosteroids usually experience cognitive alteration.
    [Show full text]
  • Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A
    Case Report DOI: 10.4274/tjh.2013.0082 Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy Pediatrik Bir Lösemi Olgusunda Tiyopurin S-Metiltransferaz *3A/*3C Polimorfizmi ile İlişkili Ağır Miyelotoksisite-Steroid Tedavisinin Etkisi Burcu Fatma Belen1, Türkiz Gürsel1, Nalan Akyürek2, Meryem Albayrak3, Zühre Kaya1, Ülker Koçak1 1Gazi University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey 2Gazi University Faculty of Medicine, Department of Pathology, Ankara, Turkey 3Kırıkkale University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey Abstract: Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C. Key Words: Myelosuppression, Thiopurine S-methyl transferase, Acute leukemia Özet: Miyelosupresyon,
    [Show full text]
  • Clinical Pharmacology of Antiмcancer Agents
    A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved.
    [Show full text]
  • Risk-Adapted Therapy for Young Children with Embryonal Brain Tumors, High-Grade Glioma, Choroid Plexus Carcinoma Or Ependymoma (Sjyc07)
    SJCRH SJYC07 CTG# - NCT00602667 Initial version, dated: 7/25/2007, Resubmitted to CPSRMC 9/24/2007 and 10/6/2007 (IRB Approved: 11/09/2007) Activation Date: 11/27/2007 Amendment 1.0 dated January 23, 2008, submitted to CPSRMC: January 23, 2008, IRB Approval: March 10, 2008 Amendment 2.0 dated April 16, 2008, submitted to CPSRMC: April 16, 2008, (IRB Approval: May 13, 2008) Revision 2.1 dated April 29, 2009 (IRB Approved: April 30, 2009 ) Amendment 3.0 dated June 22, 2009, submitted to CPSRMC: June 22, 2009 (IRB Approved: July 14, 2009) Activated: August 11, 2009 Amendment 4.0 dated March 01, 2010 (IRB Approved: April 20, 2010) Activated: May 3, 2010 Amendment 5.0 dated July 19, 2010 (IRB Approved: Sept 17, 2010) Activated: September 24, 2010 Amendment 6.0 dated August 27, 2012 (IRB approved: September 24, 2012) Activated: October 18, 2012 Amendment 7.0 dated February 22, 2013 (IRB approved: March 13, 2013) Activated: April 4, 2013 Amendment 8.0 dated March 20, 2014. Resubmitted to IRB May 20, 2014 (IRB approved: May 22, 2014) Activated: May 30, 2014 Amendment 9.0 dated August 26, 2014. (IRB approved: October 14, 2014) Activated: November 4, 2014 Un-numbered revision dated March 22, 2018. (IRB approved: March 27, 2018) Un-numbered revision dated October 22, 2018 (IRB approved: 10-24-2018) RISK-ADAPTED THERAPY FOR YOUNG CHILDREN WITH EMBRYONAL BRAIN TUMORS, HIGH-GRADE GLIOMA, CHOROID PLEXUS CARCINOMA OR EPENDYMOMA (SJYC07) Principal Investigator Amar Gajjar, M.D. Division of Neuro-Oncology Department of Oncology Section Coordinators David Ellison, M.D., Ph.D.
    [Show full text]
  • Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries Into Optimized Therapies Thai Hoa Tran1,2, Avanthi Tayi Shah3,4, and Mignon L
    Published OnlineFirst June 9, 2017; DOI: 10.1158/1078-0432.CCR-16-0115 Review Clinical Cancer Research Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies Thai Hoa Tran1,2, Avanthi Tayi Shah3,4, and Mignon L. Loh3,4 Abstract Survival of children with cancers has dramatically improved aberrant activation of signaling pathways, and epigenetic modi- over the past several decades. This success has been achieved fiers that can be targeted by novel agents. Thus, the recently through improvement of combined modalities in treatment described genomic and epigenetic landscapes of many child- approaches, intensification of cytotoxic chemotherapy for hood cancers have expanded the paradigm of precision med- those with high-risk disease, and refinement of risk stratifica- icine in the hopes of improving outcomes while minimizing tion incorporating novel biologic markers in addition to tra- toxicities. In this review, we will discuss the biologic rationale ditional clinical and histologic features. Advances in cancer for molecularly targeted therapies in genomically defined sub- genomics have shed important mechanistic insights on disease sets of pediatric leukemias, solid tumors, and brain tumors. biology and have identified "driver" genomic alterations, Clin Cancer Res; 23(18); 5329–38. Ó2017 AACR. Introduction which may represent actionable therapeutic targets. In this review, we will discuss how genomic discoveries are being translated from Survival rates for children diagnosed with cancer have the bench into the clinic, resulting in the development of precision improved substantially over the past five decades. Today, long- medicine trials for specific subtypes of pediatric hematologic term survival is expected for approximately 80% of children malignancies, solid tumors, and brain tumors.
    [Show full text]
  • Immunosuppressive Therapy DR
    OCTOBER 2017 Immunosuppressive Therapy DR. ANDREW MACKIN BVSc BVMS MVS DVSc FANZCVSc DipACVIM Professor of Small Animal Internal Medicine Mississippi State University College of Veterinary Medicine, Starkville, MS A number of established immunosuppressive agents have been used in small animal medicine for many decades. Some have justifiably fallen out of favor whereas, for others, new and promising uses have been described in the recent veterinary literature. Established “old favorites” have included cyclophosphamide, chlorambucil, azathioprine, danazol and vincristine, although cyclophosphamide and danazol are rarely used as immunosuppressive agents these days. Several potent immunosuppressive drugs developed over the past few decades in human medicine have recently made the leap to our small animal patients, and our use of drugs such as cyclosporine, leflunomide and mycophenolate is growing. Cyclophosphamide Cyclophosphamide, a cell-cycle nonspecific nitrogen mustard derivative alkylating agent, was one of the first major chemotherapeutic agents approved by the FDA over 50 years ago, and has since become very well-established in human medicine as both an antineoplastic drug and as an immunosuppressive agent. Within a few years of FDA approval in the late 1950s, the use of cyclophosphamide for the prevention of transplant rejection in experimental models and for the treatment of both neoplasia and immune-mediated diseases was described in both dogs and cats. Cyclophosphamide has persisted to this day as one of the core drugs used in many small animal cancer chemotherapeutic protocols. In contrast, after many years as one of the most commonly immunosuppressive drugs utilized to treat immune-mediated diseases in cats and dogs, the use of cyclophosphamide as an immunosuppressive agent in small animal patients has in the past two decades essentially faded away.
    [Show full text]
  • Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models Wendy L
    Cancer Therapy: Clinical Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models Wendy L. Allen,1 Vicky M. Coyle,1Puthen V. Jithesh,1Irina Proutski,1Leanne Stevenson,1Cathy Fenning,1 Daniel B. Longley,1Richard H. Wilson,1Michael Gordon,2 Heinz-Josef Lenz,2 and Patrick G. Johnston1 Abstract Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time. Experimental Design: Data analysis identified a list of genes that were acutely altered in the parental cells following SN38 treatment as well as constitutively altered in the SN38-resistant cells. Results: Independent validation of 20% of these genes by quantitative reverse transcription- PCR revealed a strong correlation with the microarray results: Pearson’s correlation was 0.781 (r2 =0.61,P < 0.000001) for those genes that were acutely altered in the parental setting following SN38 treatment and 0.795 (r2 =0.63,P < 0.000002) for those genes that were constitutively altered in the SN38-resistant cells. We then assessed the ability of our in vitro- derived gene list to predict clinical response to 5-fluorouracil/irinotecan using pretreatment metastatic biopsies from responding and nonresponding colorectal cancer patients using both unsupervised and supervised approaches. When principal components analysis was used with our in vitro classifier gene list, a good separation between responding and nonresponding patients was obtained, with only one nonresponding and two responding patients separating with the incorrect groups.
    [Show full text]
  • Open Full Page
    Research Article Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics Christine Hartford,1,2 Erick Vasquez,1 Matthias Schwab,1,7 Mathew J. Edick,1,6 Jerold E. Rehg,3 Gerard Grosveld,4 Ching-Hon Pui,2,5,6 William E. Evans,1,5,6 and Mary V. Relling1,5,6 Departments of 1Pharmaceutical Sciences, 2Hematology-Oncology, 3Pathology, and 4Genetics, and 5Hematologic Malignancies Program, St. Jude Children’s Research Hospital, 6University of Tennessee, Memphis, Tennessee; and 7Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany Abstract TPMT polymorphism. Inherited as an autosomal codominant trait The recessive deficiency in thiopurine methyltransferase (6–8), TPMT activity in erythrocytes (reflective of other tissues as (TPMT), caused by germ-line polymorphisms in TPMT, can well; refs. 7, 9–11) exhibits a trimodal population frequency cause severe toxicity after mercaptopurine. However, the distribution (12–14). TPMT activity is inversely related to the significance of heterozygosity and the effect of the polymor- concentration of active thioguanine metabolites after administra- phism on thioguanine or in the absence of thiopurines is not tion of thiopurines (4). The rare homozygous deficient individuals known. To address these issues, we created a murine knockout develop extreme myelosuppression, which can be fatal when given of Tpmt. Pharmacokinetic and pharmacodynamic studies of usual doses of thiopurines (15), necessitating a 10-fold dosage À À mercaptopurine and thioguanine were done in Tpmt / , decrease to prevent such toxicity (16). Heterozygotes, constituting À Tpmt+/ , and Tpmt+/+ mice and variables were compared 10% of the population, often exhibit an intermediate degree of among genotypes.
    [Show full text]
  • Pre-Clinical Metabolism Studies with Fenretinide in Paediatric Cancer
    Pre-Clinical Metabolism Studies with Fenretinide in Paediatric Cancer Nicola Ann Illingworth Thesis Submitted for the Degree of Doctor of Philosophy August 2011 Northern Institute for Cancer Research Faculty of Medical Sciences The Medical School Newcastle University Abstract Fenretinide (4-HPR) is a retinoic acid analogue used in clinical trials for the treatment of neuroblastoma and Ewing’s sarcoma. The work described involves investigations into factors that may impact on 4-HPR drug disposition. Metabolism of 4-HPR is of particular interest due to production of the active metabolite 4’-oxo 4-HPR and the clinical challenge of obtaining consistent 4-HPR plasma concentrations. The enzymes involved in 4-HPR metabolism were characterised and the impact of metabolism on efficacy in neuroblastoma and Ewing’s sarcoma cell lines assessed. In addition, the potential for 4-HPR to act as a substrate for common drug transporters was explored. 4-HPR was metabolised to 4’-oxo 4-HPR and 4’-OH 4-HPR primarily by CYPs 3A4, 3A5 and 2C8. Genetic variance in CYP2C8 affected oxidative metabolism, with much lower affinity for 2C8*4 (km of 59.8µM compared to 19.3µM for wild-type), and may be of clinical relevance. Both 4-HPR and 4’-oxo 4-HPR were glucuronidated. 4-HPR was glucuronidated by UGTs 1A1, 1A3 and 1A6, whilst 4’-oxo 4-HPR was glucuronidated by UGTs 1A1, 1A3, 1A8 and 1A9. However, very high Km values were observed (ranging from 389µM to 716µM for 4-HPR). Methylation of 4-HPR to the major metabolite 4-methoxyphenyl retinamide (4-MPR) was determined to be carried out by amine N-methyltransferases.
    [Show full text]
  • Pathway-Based Analysis of Genome-Wide Association Data
    fphar-09-00158 March 9, 2018 Time: 17:6 # 1 ORIGINAL RESEARCH published: 13 March 2018 doi: 10.3389/fphar.2018.00158 Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients Edited by: Rick Kittles, Behzad Bidadi1†, Duan Liu1, Krishna R. Kalari2, Matthias Rubner3, Alexander Hein3, Irell and Manella Graduate School Matthias W. Beckmann3, Brigitte Rack4, Wolfgang Janni5, Peter A. Fasching3, of Biological Sciences, United States Richard M. Weinshilboum1 and Liewei Wang1* Reviewed by: Ming Ta Michael Lee, 1 Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Geisinger Health System, Rochester, MN, United States, 2 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, United States Mayo Clinic, Rochester, MN, United States, 3 Department of Gynecology and Obstetrics, University Hospital Erlangen, Ken Batai, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany, 4 Department of Gynecology and Obstetrics, University of Arizona, United States Ludwig-Maximilians-Universität München, Munich, Germany, 5 Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany *Correspondence: Liewei Wang [email protected] Neutropenia secondary to chemotherapy in breast cancer patients can be life- † Present address: threatening and there are no biomarkers available to predict the risk of drug-induced Behzad Bidadi, Merck & Co., Inc., North Wales, PA, neutropenia in those patients. We previously performed a genome-wide association United States study (GWAS) for neutropenia events in women with breast cancer who were treated with 5-fluorouracil, epirubicin and cyclophosphamide and recruited to the SUCCESS- Specialty section: This article was submitted to A trial.
    [Show full text]