DOCSLIB.ORG

Genomics-Driven Healthcare Trends in Disease Prevention and Treatment Genomics-Driven Healthcare Yashwant Pathak Editor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genomics-Driven Healthcare Trends in Disease Prevention and Treatment Genomics-Driven Healthcare Yashwant Pathak Editor Yashwant Pathak Editor Genomics-Driven Healthcare Trends in Disease Prevention and Treatment Genomics-Driven Healthcare Yashwant Pathak Editor Genomics-Driven Healthcare Trends in Disease Prevention and Treatment Editor Yashwant Pathak University of South Florida Health College of Pharmacy Tampa, FL USA ISBN 978-981-10-7505-6 ISBN 978-981-10-7506-3 (eBook) https://doi.org/10.1007/978-981-10-7506-3 Library of Congress Control Number: 2018945057 © Springer Nature Singapore Pte Ltd. 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Adis imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Dedicated to the loving memory of my parents, and to Param Pujaniya, Dr Keshav Baliram Hedgewar, and Mananiya Madhukar Limaye, who gave me proper direction; my wife Seema, who gave a positive meaning to my life; and my son Sarvadaman, who has given my life a golden lining. Foreword Two general treatment approaches are employed in the pharmacotherapeutic man- agement of disease. One is the “trial and error” approach, employed for drug treat- ments of diseases such as hypertension, arrhythmias, diabetes, esophageal reflux, depression, and schizophrenia. For these diseases, a small number of drugs provide evidence-based first-line therapies. Finding the most effective drugs for a given patient is often done through “trial and error”, and it can often take months to accomplish the desired therapeutic outcome. The other approach to the drug management of disease is a “per-protocol” approach, where the treatment for a given disease is essentially the same for every- one with that diagnosis. Examples of diseases treated by this approach include most cancers, heart failure, myocardial infarction, and organ transplantation. In both sce- narios, a certain percentage of patients will have no benefit from a given medication, or may experience serious adverse effects. One of the major reasons for inter-individual variations in drug responses is the presence of genetic variations that result in proteins with variable activities. Polymorphism is the occurrence, in the same population, of two or more alleles at one locus, each with a frequency of >1%. Genetic variations can be a result of RNA splicing; gene transcription; and nucleotide repeats, insertions, deletions, and single nucleotide polymorphisms (SNPs) that can alter the amino acid sequences of the encoded proteins. Pharmacogenomics is the study of how changes in the genome-wide DNA sequence affect drug responses. This book systematically updates our current phar- macogenomic knowledge of important drug targets, drug transporters, and drug- metabolizing enzymes to better understand currently available evidence for this recently established discipline and its potential application in personalized medicine. Recent advances in molecular research have revealed many of the genes that encode drug targets that demonstrate genetic polymorphism. These variations, in many cases, have altered the target’s sensitivity to the specific drug molecule, and thus have a profound effect on drug efficacy and toxicity. For instance, theβ 2- adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically signifi- cant genetic variation in drug targets. The variable number tandem repeat polymorphisms in the serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. With respect to drug transport polymorphisms, the vii viii Foreword most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on its clinical impact is limited. Polymorphisms in drug transporters may change a drug’s distribution, excretion, and response. Polymorphisms in the cytochrome P450 (CYP) family may have the most impact on the fate of drugs. CYP2D6, CYP2C19, and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in the phase I metabolism of drugs, since nearly 80% of the drugs in use today are metabolized by these enzymes. Extensive polymorphism also occurs in a majority of phase II drug-metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyltransferase (TPMT), which catalyzes the S-methylation of thiopurine drugs. The promise of pharmacogenomics lies in its potential to identify the right drug at the right dose for the right individual. The role of genomics can be helpful in understanding disease occurrence and progression, the medical needs of specific ethnic/racial groups, and the medical needs of distinctive populations with specific gene pools. Genomics can assist in effective disease management, and finally it can help to achieve optimal care for both healthy populations and patient populations. The 18 chapters of this book cover various aspects of the application of pharma- cogenomics for disease prevention and for better health care. This area of research is growing significantly and there was a need for such a book. I am sure the scientific community will welcome the efforts of Dr Yashwant Pathak, who has edited this book, and I would like to congratulate him for his hard work in bringing out his volume. I wish all the best for the book and I am sure it will contribute to the wealth of knowledge in this area. Kevin B. Sneed USF Health Tampa, FL, USA USF College of Pharmacy Tampa, FL, USA Preface Omics-Driven Trends in Disease Prevention and Better Healthcare With the advent of “Omics” sciences, such as proteomics, pharmacogenomics, pharmaco-genetics, metabolomics, transcriptomics, and bioinformatics, their appli- cation in genomic studies has initiated new pathways in the areas of drug design, discovery, delivery, and disposition, thus creating a knowledge base that will be helpful to build strategies for disease prevention and better health for all. This book addresses various trends in science that can or will lead to disease prevention, disease mitigation, and better health for the masses, based on the Omics revolution we have been witnessing since the publication of genome studies in the early part of this century. The book covers Omics-driven trends not only in drugs but also in pharmaceuticals for disease prevention and better healthcare. There is also a special focus on nutrition and nutraceuticals. This book has 18 chapters written by leading researchers in this field and they have addressed various issues related to genomics-driven trends in disease preven- tion and better healthcare. The chapters deal with pharmacogenomics and pharma- coepigenetics and their impact on therapeutic strategies; drug discovery after the genomic revolution; genomics and transporters in drug discovery, delivery, and dis- position; SNP molecular approaches; genomics and metabolizing enzymes; the impact of genomics on drug discovery and clinical medicine; neurodegenerative diseases and genomics; genomics and lung diseases; bioinformatics approaches for better health care, and new approaches for the prevention of diseases, based on genomic knowledge. I feel this book will be a significant contribution toward the understanding of genomics and its implications in disease prevention and better healthcare. I would like to thank personally all the contributors whose hard work led to this book—their hard work in providing the chapters on time is greatly appreciated. My special thanks to Dean Kevin B. Sneed for providing the foreword for this book, and I thank the group of Springer publishers who have worked hard to make this project successful. I also thank the University of South Florida and the College of Pharmacy for providing me with support to complete the book project. ix x Preface My personal thanks to my family, who always have to sacrifice their time for such endeavors; I always owe them a lot. My special personal thanks to Carolyn Honour, Cameron Wright, Ellen Blasig, Palani Murugesan, and all the other Springer Nature staff who helped to get the book ready for production. If the readers find any mistakes or have suggestions about improvements, kindly forward these to me and I will try to incorporate any changes in the second edition. Tampa, FL, USA Yashwant Pathak Contents 1 Rethinking Drug Discovery and Targeting After the Genomic Revolution . 1 Dharmesh R. Chejara, Ravindra V. Badhe, Pradeep
Load more

Recommended publications
  • Mechanisms and Strategies to Overcome Multiple Drug Resistance in Cancer
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 580 (2006) 2903–2909 Minireview Mechanisms and strategies to overcome multiple drug resistance in cancer Tomris Ozben* Akdeniz University, Faculty of Medicine, Department of Biochemistry, 07070 Antalya, Turkey Received 30 January 2006; accepted 9 February 2006 Available online 17 February 2006 Edited by Horst Feldmann The cytotoxic drugs that are most frequently associated with Abstract One of the major problems in chemotherapy is multi- drug resistance (MDR) against anticancer drugs. ATP-binding MDR are hydrophobic, amphipathic natural products, such as cassette (ABC) transporters are a family of proteins that medi- the taxanes (paclitaxel and docetaxel), vinca alkaloids (vinorel- ate MDR via ATP-dependent drug efflux pumps. Many MDR bine, vincristine, and vinblastine), anthracyclines (doxorubicin, inhibitors have been identified, but none of them have been pro- daunorubicin, and epirubicin), epipodophyllotoxins (etoposide ven clinically useful without side effects. Efforts continue to dis- and teniposide), antimetabolites (methorexate, fluorouracil, cover not toxic MDR inhibitors which lack pharmacokinetic cytosar, 5-azacytosine, 6-mercaptopurine, and gemcitabine) interactions with anticancer drugs. Novel approaches have also topotecan, dactinomycin, and mitomycin C [4,6–8]. been designed to inhibit or circumvent MDR. In this review, Overexpression of ATP-binding cassette (ABC) transporters the structure and function of ABC transporters and development has been shown to be responsible for MDR [5]. Therefore eluci- of MDR inhibitors are described briefly including various ap- dation of the structure and function for each ABC transporter is proaches to suppress MDR mechanisms.
    [Show full text]
  • Expression of Cytokeratin Confers Multiple Drug Resistance (Multidrug Resance/Cytoskeleton) PATRICIA A
    Proc. Nati. Acad. Sci. USA Vol. 91, pp. 5311-5314, June 1994 Pharmacology Expression of cytokeratin confers multiple drug resistance (multidrug resance/cytoskeleton) PATRICIA A. BAUMAN*, WILLIAM S. DALTON*t, JOHN M. ANDERSONt, AND ANNE E. CRESSO§ Departments of *Pharmacology and Toxicology, tMedicine, and *Radiation Oncology, The University of Arizona, The Arizona Cancer Center, Tucson, AZ 85724 Communicated by Gertrude B. Elion, February 23, 1994 (received for review October 21, 1993) ABSTRACT The cytokeratin network is an extensive fda- We utilized a mouse fibroblast cell line and a transfected mentous structure in the cytoplasm whose biological function(s) variant expressing cytokeratins 8 and 18 (9) to test whether is unknown. Based upon previous data showing the modifica- cytokeratin expression could alter the cell survival response tion ofcytokeratin by mitoxantrone, we investigated the ability to six different chemotherapeutic drugs. of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. We have compared the MATERIALS AND METHODS survival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence Tumor Cell Lines, Growth Curves, and Cell Cycle Distri- of chemotherapeutic drugs. The expression of cytokeratins 8 butions. Parental L cells and transfected LK8+18 cells were and 18 conferred a multiple drug resistance phenotype on cells obtained from Robert Oshima (La Jolla Cancer Research exposed to mitoxantrone, doxorubicin, methotrexate, melpha- Foundation, La Jolla, CA) and maintained as described (9). Ian, Colcemid, and vincristine. The degree of drug resistance Mock transfectants (LPBMOC) were created by simultane- was 5-454 times that of parental cells, depending upon the ous calcium phosphate transfection of pGEM-3 (Promega) agent used.
    [Show full text]
  • Association of Genetic and Nongenetic Variabilities With
    ASSOCIATION OF GENETIC AND NONGENETIC VARIABILITIES WITH PHENYTOIN AND CARBAMAZEPINE RESPONSE PHENOTYPES A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY PORNPIMOL KIJSANAYOTIN IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY RICHARD BRUNDAGE ADVISOR APRIL, 2012 © Pornpimol Kisanayotin 2012 Acknowledgements It has been a long time since I decided to pursue the PhD study in the US after receiving a scholarship from the Royal Thai Government. Without the following people I could not be able to follow my dream to successfully conduct this pharmacogenetic study for my PhD dissertation. First, I would like to express my deep gratitude to Prof. James C Cloyd and Prof. Ilo E Leppik for not only giving me the opportunity to carry out this research work by using data sets from the P50 program projects but also all their academic and financial support. I also would like to express my special gratitude to Prof. Richard Brundage, my advisor, for his kindness, academic advice as well as all his support and encouragement. I express my gratitude to Prof. William S Oetting, my co-advisor for his academic advice and encouraging words. I also express my gratitude to Prof. Richard King for allowing me to use his laboratory, facilities and providing technical support for genotyping work. I would like to thank Dr. Angela K Burnbaum and all the staff at the Epilepsy Reseach and Education Program, University of Minnesota for all their assistance in research. I would like to thank Dr. Elving Anderson for his kindness and academic advice.
    [Show full text]
  • Multiple Drug Resistance: a Fast-Growing Threat
    Review Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2019.21.003572 Multiple Drug Resistance: A Fast-Growing Threat Eremwanarue Aibuedefe Osagie1,2* and Shittu Hakeem Olalekan1 1Department of Plant Biology and Biotechnology, University of Benin, Nigeria 2Lahor Research Laboratories and Diagnostics Centre, Nigeria *Corresponding author: Eremwanarue Aibuedefe Osagie, Department of Plant Biology and Biotechnology, University of Benin, Nigeria ARTICLE INFO Abstract Received: September 03, 2019 The spread of antibiotic resistant bacteria is a growing problem and a public health Published: September 10, 2019 issue. Over the years, various genetic mechanisms concerned with antibiotic resistance have been identified to be natural and acquired resistance. The natural resistance Citation: Eremwanarue Aibuedefe Osag- ie, Shittu Hakeem Olalekan. Multiple Geneticinvolved Elements mutation [MGEs] via target such modification,as plasmid, transposon reduced permeability, and integrons efflux genetic system elements and Drug Resistance: A Fast-Growing Threat. on the other hand, acquired resistance via horizontal gene tranfer include Moblie Biomed J Sci & Tech Res 21(2)-2019. Integrons are widely distributed, especially in Gram-negative bacteria; they are carried BJSTR. MS.ID.003572. bythat Mobile can acquire, Genetic exchange, Elements and such express as plasmids, genes embeddedand transposons, within whichGene Cassettespromote [GC].their spread within bacterial communities and have been studied mainly in the clinical setting Keywords: Antibiotics; Multiple Drug for their involvement in antibiotic resistance, their role in the environment is now an Resistant Bacteria; Mobile Genetic increasing focus of attention. The aim of this review is to educate the populise about Element; Integrons Plasmid the mechanisms of multiple drug resistance bacteria isolates and the danger ahead if appropriate regulations are not put in place especially in developing country like Nigeria.
    [Show full text]
  • Inventory of Projects
    INVENTORY OF PROJECTS PROGRESS REPORT: IMPLEMENTATION OF A PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE PROGRESS THROUGH 2007 FOCUS AREA I: SURVEILLANCE ACTION ITEM #1: DETERMINE WHICH ORGANISMS AND SUSCEPTIBILITY TO SPECIFIC ANTIMICROBIAL DRUGS SHOULD BE UNDER SURVEILLANCE AND CREATE A MECHANISM FOR PERIODIC UPDATING OF THIS LIST. PROJECT TITLE: PUBLIC HEALTH SURVEILLANCE • Agency: CDC, USDA, FDA, DoD, VA • Description: Organisms currently under public health surveillance for antimicrobial resistance include: Campylobacter, E. coli O157:H7, Gram negative and Gram positive organisms causing health care associated infections, group A Streptococcus, group B Streptococcus, Haemophilus influenzae, Helicobacter pylori, HIV, Influenza, Malaria, Mycobacterium tuberculosis, Neisseria gonorrhoeae, Neisseria meningitidis, Salmonella, Shigella, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Trichomonas vaginalis, and Vancomycin Resistant Enterococcus. Organisms are added to this list when resistance emerges as a public health problem, as tools are developed for detecting resistance, and when there is capacity at the appropriate level. On August 30, 2006, FDA cleared a new test for the detection of vancomycin resistant Enterococci (VRE) by detecting vanA and vanB genes using an automated real-time PCR Instrument. It is indicated for use for patients at risk for VRE colonization. • Results: Ongoing. See Executive Summary and Surveillance Data (to be released following public comment period, summer 2007). PROJECT: CDC ANTIMICROBIAL RESISTANCE SURVEILLANCE ACTIVITIES MEETING • Agency: CDC • Description: The CDC Office of Antimicrobial Resistance, in response to the recently held Antimicrobial Resistance Task Force consultants meeting, convened an internal AR surveillance meeting to explore ways for programs to strengthen and enhance their current surveillance efforts. By sharing successes and failures and exploring potential collaborations, we may be able to increase the impact and utility of our overall surveillance programs.
    [Show full text]
  • Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance
    Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance by Douglas McMillan A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto © Copyright by Douglas McMillan 2018 Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance Douglas McMillan Doctor of Philosophy Graduate Department of Pharmacology and Toxicology University of Toronto 2018 Abstract Cytochrome P450 2D (CYP2D) is a subfamily of enzymes expressed in both liver and brain that metabolizes clinically used drugs, neurotoxins, and endogenous neurochemicals. Opioid analgesics are metabolized by CYP2D to more potent analgesic metabolites, and variation in this metabolism may alter opioid response. While human CYP2D expression in the liver is primarily regulated by genetics, brain CYP2D activity may be altered by genetics, environmental inducers, and hormonal regulation. Smokers have higher brain, but not liver, CYP2D and nicotine induces rat brain, but not liver, CYP2D. This thesis investigated the impact of altering rat brain CYP2D activity in vivo on the brain metabolism of opioids and resulting analgesia. Rats were administered opioids and analgesia was measured; drug levels were assessed in brain and plasma after sacrifice, or in brain in vivo by microdialysis. Rat brain CYP2D was inhibited by intracerebroventricular injection of a CYP2D mechanism-based inhibitor or induced by seven-day subcutaneous nicotine treatment. We found that rat brain CYP2D activation of codeine to morphine mediates acute codeine analgesia; inhibiting brain CYP2D decreased, and inducing brain CYP2D increased, brain morphine from codeine and resulting codeine analgesia. In a rat model of codeine analgesic tolerance, inducing brain CYP2D increased acute analgesia and the rate of analgesic tolerance, producing a greater absolute decrease in analgesia per codeine dose.
    [Show full text]
  • Antibiotic Resistance: Mechanisms and New Antimicrobial Approaches
    Antibiotic Resistance This page intentionally left blank Antibiotic Resistance Mechanisms and New Antimicrobial Approaches Kateryna Kon, MD, PhD Department of Microbiology, Virology, and Immunology Kharkiv National Medical University Kharkiv, Ukraine Mahendra Rai, PhD Biotechnology Department SGB Amravati University Maharashtra, India AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright r 2016 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein.
    [Show full text]
  • Assessment of the Antibiotic Resistance Effects of Biocides
    Scientific Committee on Emerging and Newly Identified Health Risks SCENIHR Assessment of the Antibiotic Resistance Effects of Biocides The SCENIHR adopted this opinion at the 28th plenary on 19 January 2009 after public consultation. 1 Antibiotic Resistance Effects of Biocides About the Scientific Committees Three independent non-food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commission's attention to the new or emerging problems which may pose an actual or potential threat. They are: the Scientific Committee on Consumer Products (SCCP), the Scientific Committee on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), and are made up of external experts. In addition, the Commission relies upon the work of the European Food Safety Authority (EFSA), the European Medicines Evaluation Agency (EMEA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCENIHR Questions concerning emerging or newly-identified risks and on broad, complex or multi- disciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health and related issues not covered by other Community risk-assessment bodies. In particular, the Committee addresses questions related to potential risks associated with interaction of risk factors, synergic effects, cumulative effects, antimicrobial resistance, new technologies such as nanotechnologies, medical devices, tissue engineering, blood products, fertility reduction, cancer of endocrine organs, physical hazards such as noise and electromagnetic fields and methodologies for assessing new risks.
    [Show full text]
  • Background Paper 6.1 Antimicrobial Resistance
    Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by Per Nordberg, Dominique L. Monnet, Otto Cars Background Paper 6.1 Antimicrobial resistance By Emma M. Lodato, Boston University and Warren Kaplan, PhD, JD, MPH, Boston University April 2013 Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Table of Contents Acknowledgements ............................................................................................................................................ 3 Acronyms .............................................................................................................................................................. 4 1. Introduction ................................................................................................................................................. 5 2. Why does the problem persist? ................................................................................................................ 6 2.1 New variants of resistance have continued to emerge .................................................................. 7 2.2 Transmission of antibiotic-resistant bacteria .................................................................................. 8 2.3 Antibiotic misuse continues to be a challenge ................................................................................ 9 3. Epidemiological trends ..........................................................................................................................
    [Show full text]
  • The Role of Abcb1 and Abcb5 in Paediatric Inflammatory
    THE ROLE OF ABCB1 AND ABCB5 IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE Thesis submitted in accordance with the requirements of the University of Liverpool NOVEMBER 2018 THE UNIVERSITY OF LIVERPOOL Wolfson Centre for Personalized Medicine Department of Clinical and Molecular Pharmacology Institute of Translational Medicine, University of Liverpool And Alder Hey Children’s Hospital NHS Foundation Trust Research Work by Doctor Anastasia Konidari Consultant Paediatric Gastroenterologist Alder Hey Children’s Hospital NHS Foundation Trust Abstract ABC transporters play an important role in drug disposition. ABCB1, the most studied representative member of this transporter superfamily, can influence drug response and shape multi-drug resistance in cancer and various diseases including inflammatory bowel disease. Adult studies have shown inter-individual variability in expression between patients with inflammatory bowel disease and healthy controls, which can be modified by corticosteroid administration, a common treatment agent for inflammatory bowel disease. ABCB5 is a novel transporter highly homologous to ABCB1. This thesis focusses on an inception pilot cohort of children and young people with newly diagnosed inflammatory bowel disease and healthy controls. The purpose of this thesis is to investigate the expression of ABCB1 and ABCB5 in vitro and ex vivo, to test the hypothesis that both are important in children with inflammatory bowel disease with respect to expression, to investigate how expression varies with genotype, and to explore the possible role of ABCB5 as corticosteroid transporter. De novo production of stable and transient overexpressing mammalian ABCB5 clones confirmed high gene expression at the mRNA level, but no ABCB5 protein isoforms were detectable, despite repeated attempts and investigation of human malignant cell derived ABCB5 expressing clones donated by experts in the field.
    [Show full text]
  • Final Version-Thesis-Xin
    Department of Oncology and Pathology, Cancer Centrum Karolinska Karolinska Institutet, Stockholm, Sweden STUDIES OF OVERCOMING ACQUIRED RESISTANCE: MOLECULAR MECHANISMS AND DEVELOPMENT OF NOVEL DRUGS Xin Wang 王欣 Stockholm 2014 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Åtta.45 Tryckeri © Xin Wang, 2014 ISBN 978-91-7549-555-2 To my family ABSTRACT Chemotherapeutic agents have become widely applied for treatment of various types of malignancies. Drug resistance unfortunately remains as a major obstacle for the effectiveness of chemotherapy. Cancer drug resistance includes two broad categories: intrinsic and acquired. In this thesis I have examined the problem of acquired drug resistance and have aimed to develop novel approaches to overcome acquired resistance. Clofarabine is a second-generation nucleoside analogue which has been employed primarily for the treatment of hematological malignancies. In paper I, we found that clofarabine inhibited [14C]-thymidine uptake, presumably by decreasing DNA synthesis. Clofarabine was also found to induce apoptosis of a solid tumor cell line, a finding which may open new fields of application of this drug. In paper II, 5’-nucleotidases, a family of enzymes known to confer resistance to nucleoside analogues, were found to be expressed at various levels in samples from CLL patients. Moreover, degradation of fludarabine monophosphate was found to be associated with CN2 activity, and degradation of cladribine monophosphate was associated with CN1 activity. This result helps to explain why some leukemic patients may show resistance to different nucleoside analogues. In paper III, we screened the RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 for the response to 3,000 chemically diverse compounds.
    [Show full text]
  • Repositioning of Tyrosine Kinase Inhibitors As Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance
    Cancers 2014, 6, 1925-1952; doi:10.3390/cancers6041925 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance Yi-Jun Wang, Yun-Kai Zhang, Rishil J. Kathawala and Zhe-Sheng Chen * Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; E-Mails: [email protected] (Y.-J.W.); [email protected] (Y.-K.Z.); [email protected] (R.J.K.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-718-990-1432; Fax: +1-718-990-1877. Received: 31 July 2014; in revised form: 4 September 2014 / Accepted: 11 September 2014 / Published: 29 September 2014 Abstract: The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance. Keywords: multidrug resistance; ABC transporters; tyrosine kinase inhibitor; clinical relevance; pharmacogenomics 1. Introduction Cancer, also known as malignant neoplasm or tumor, is the second most leading cause of death after cardiovascular diseases in United States and developing countries.
    [Show full text]