DNA Methylation and Cancer Therapy by Moshe SzyfDNA Methylation and Cancer Therapy by Moshe Szyf

DNA Methylation and Cancer Therapy

byMoshe Szyf

Paperback | December 6, 2010

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This book provides a comprehensive analysis of implications of DNA methylation on cancer diagnosis and cancer therapy. This unique volume focuses on cancer therapy by thoroughly dissecting the basic principles of DNA methylation in cancer from molecular mechanisms to clinical trials. The chapters are written by leading experts in the field and are designed to provide the reader with the necessary background to evaluate critically the potential of DNA methylation in cancer therapy. Key features of this book include discussions of the following topics:The molecular machinery responsible for DNA methylation and their impact on gene expression and tumorigenesis. The emerging relation between DNA methylation and chromatin modifying proteins.How the relationship between DNA methylation and chromatin modifying proteins might clarify the mechanisms and therapeutic implications of aberrant DNA methylation in cancer. Illustrations of the diagnostic potential of methylation in cancer and novel tools for using methylation profiling of cancers.The therapeutic potential of the DNA methylation machinery and novel attempts to target the DNA methylation enzymes in anticancer therapy.This book will be of interest to a wide audience, including oncologists, researchers and clinicians, and graduate students in the fields of oncology, molecular biology, and cancer therapy, as well as researchers and decision-makers in industry focusing on anticancer drugs and diagnosis.
Title:DNA Methylation and Cancer TherapyFormat:PaperbackDimensions:254 pages, 9.21 × 6.14 × 0.27 inPublished:December 6, 2010Publisher:Springer USLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:1441934162

ISBN - 13:9781441934161

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Table of Contents

Preface ................................................................................................ xiii1. DNA Methylation: Three Decades in Search of Function ...................... 1Aharon RazinDNA Methylation in Prokaryotes.......................................................... 1DNA Methylation in Eukaryotes ........................................................... 2Methylation and Embryogenesis ............................................................ 2DNA Methylation and Imprinting ........................................................ 4DNA Methylation in Gene Silencing .................................................... 4DNA Methylation and Disease.............................................................. 5Reflections ............................................................................................. 82. Epigenetic Mechanisms of Gene Regulation: Relationshipsbetween DNA Methylation, Histone Modification,and Chromatin Structure ..................................................................... 13Keith D. RobertsonThe Mammalian DNA Methyltransferases (DNMTs) ......................... 14Interaction between DNMTs and Other Proteins ............................... 16DNA Methylation and DNA Replication ............................................ 20Links between DNA Methylation and Histone Modification .............. 20DNA Methylation and Histone Methylation ...................................... 21DNMTs As Transcriptional Corepressors ........................................... 22DNA Methylation and Chromatin Remodeling .................................. 243. DNA Hypo- vs. Hypermethylation in Cancer: Tumor Specificity,Tumor Progression, and Therapeutic Implications .............................. 31Melanie Ehrlich and Guanchao JiangAre There Tumor-Specific DNA Hypomethylation Profiles Likethe Tumor-Specific DNA Hypermethylation Profiles? .................... 32Is There a Relationship between Cancer-Associated DNA,Hypomethylation and DNA Hypermethylation? ............................. 34Is DNA Hypomethylation, Like DNA Hypermethylation,Sometimes Associated with Tumor Progression? .............................. 35Might There Be Deleterious Consequences of Introducing DNAHypomethylation in the Genome As a Cancer Therapy? ................. 374. DNA Methylation in Urological Cancers ............................................. 42Wolfgang A. Schulz and Hans-Helge SeifertAn Overview of Urological Cancers ..................................................... 42A Description of DNA Methylation Changesin Urological Malignancies .............................................................. 44A Global View of DNA Methylation Alterationsin Urological Cancers ...................................................................... 47Causes of Altered DNA Methylation in Urological Cancers ................ 48Consequences of Altered DNA Methylation in Urological Cancers ....... 50DNA Methylation in Diagnosis and Therapy of Urological Cancers ...... 51Szyf MIU Front Matter 9/15/04, 2:29 PM 55. DNA Methylation in Colorectal Cancer ............................................... 59Jeremy R. Jass, Vicki L.J. Whitehall, Joanne Young and Barbara A. LeggettRelevance of Familial Models of Colorectal Cancerto Sporadic Neoplasia ...................................................................... 60DNA Microsatellite Instability ............................................................ 60Mechanisms Underlying Microsatellite Instabilityin Colorectal Cancer ........................................................................ 61The Methylator Phenotype in Colorectal Neoplasia ............................ 62Are Subjects Genetically Predisposed to Methylationof Colorectal Mucosa? ..................................................................... 64Morphologic Counterparts of the Methylator Phenotype .................... 64Serrated Pathway of Colorectal Neoplasia ............................................ 65Can DNA Methylation Be Reversed Spontaneously? ........................... 656. CpG Island Hypermethylation of Tumor Suppressor Genesin Human Cancer: Concepts, Methodologies and Uses ........................ 69Michel Herranz and Manel EstellerConcepts ............................................................................................. 69Methodologies ..................................................................................... 76Translational Studies of CpG Island Hypermethylation:From the Bench to the Bedside ....................................................... 80Conclusions ......................................................................................... 817. The Loss of Methyl Groups in DNA of Tumor Cells and Tissues:The Immunochemical Approach .......................................................... 85Alain Niveleau, Chandrika Piyathilake, Adriana de Capoa,Claudio Grappelli, Jean-Marc Dumollard, Lucien Frappartand Emmanuel DrouetResults ................................................................................................. 868. Identifying Clinicopathological Association of DNAHypermethylation in Cancers Using CpG Island Microarrays ........... 107Susan H. Wei, Timothy T.-C. Yip, Chuan-Mu Chenand Tim H.-M. HuangGenomic Targets for DMH and MTA .............................................. 109DMH and Its Applications ................................................................ 109MTA and Its Applications ................................................................. 1139. Methylation Analysis in Cancer: (Epi)Genomic Fast Trackfrom Discovery to Clinical Routine .................................................... 117Carolina Haefliger, Sabine Maier and Alexander OlekDNA Methylation and Carcinogenesis .............................................. 117Methylation Profile in Human Cancer .............................................. 118Technological Approaches for DNA Methylation Study:High Throughput Analysis ............................................................ 119Sensitive Detection ............................................................................ 122Szyf MIU Front Matter 9/15/04, 2:29 PM 610. Regulation of DNA Methyltransferases in Cancer .............................. 125Nancy Detich and Moshe SzyfTranscriptional Regulation of DNMTs ............................................. 126Regulation by the RAS Signaling Pathway ......................................... 127APC-TCF Pathway ........................................................................... 128Feedback Regulation ......................................................................... 129Differential Regulation of the DNMTs during Cell Growth ............. 129Regulation by Viral Infection ............................................................ 130Simian Virus 40 (SV40) .................................................................... 131Epstein-Barr Virus (EBV) .................................................................. 132Human Immunodeficiency Virus Type 1 (HIV-1) ............................ 132Cell Differentiation and DNMT1 ..................................................... 132Upregulation of DNMT1 ................................................................. 132Downregulation of DNMT1 ............................................................. 133Regulation through Protein Interactions ............................................ 134PCNA ............................................................................................... 134Rb ..................................................................................................... 135Interactions between the DNMTs ..................................................... 13511. Inhibition of Poly(ADP-Ribosyl)ation AllowsDNA Hypermethylation .................................................................... 142Anna Reale, Giuseppe Zardo, Maria Malanga, Jordanka Zlatanovaand Paola CaiafaPoly(ADP-Ribosyl)ation .................................................................... 143Block of Poly(ADP-Ribosyl)ation Induces in Vivo DNAHypermethylation ......................................................................... 146Atomic Force Microscopy (AFM) Studies of the Effect of DNAMethylation on Chromatin Fiber Structure ................................... 148How Is Poly(ADP-Ribosyl)ation Involved in Protecting DNAMethylation Pattern ...................................................................... 14912. The Role of Active Demethylation in Cancer and ItsTherapeutic Potential ......................................................................... 156Moshe Szyf, Paul M. Campbell, Nancy Detich, Jing Ni Ou,Stefan Hamm and Veronica BovenziGlobal Hypomethylation in Cancer .................................................. 157Global Hypomethylation in Cancer; Single Copy and Multiple CopySequences Are Hypomethylated in Multiple Tumor Types ........... 157Mechanisms Responsible for Hypomethylation in Cancer ................. 158The Possible Role of a Demethylase; DNA MethylationIs a Reversible Reaction ................................................................. 158Resolving the Paradox of the Coexistence of RegionalHypermethylation and Global Hypomethylation in Cancer;Role of Chromatin Structure ......................................................... 162Possible Role of Global Hypomethylation in Cancer ......................... 165Mechanisms Whereby Hypomethylation Enhances Tumorigenesis ... 167The Therapeutic Implications of Global Hypomethylation ............... 169MBD2/Demethylase As an Anticancer Target ................................... 171Szyf MIU Front Matter 9/15/04, 2:29 PM 713. Purine Analogues and Their Role in Methylationand Cancer Chemotherapy ................................................................. 178Katherine L. Seley and Sylvester L. MosleyDNA Methylation and SAHase Inhibition ........................................ 178Nucleoside Inhibitors ........................................................................ 180Carbocyclic Nucleoside ..................................................................... 181Enzyme Inhibition and Cell Differentiation ...................................... 18214. DNA Methyltransferase Inhibitors: Paving the Wayfor Epigenetic Cancer Therapeutics .................................................... 187Gregory K. Reid and A. Robert MacLeodDNA Methylation: Discovery of the First Epigenetic Modifier ......... 187DNA Methylation and Cancer: A Correlation ................................... 188The DNA Methyltransferase Family of Enzymes ............................... 190DNA Methylation an Active Player in Oncogenesis: Validationof DNMT1 As a Therapeutic Cancer Target ................................. 191Isotype-Selective Inhibition of DNMTs: Antisense to SiRNA ........... 192Medicinal Chemistry of Oligonucleotides: Towards Antisense Drugs ... 195DNA Methyltransferase Inhibitors: Cancer Specificityand Potential Therapeutic Window ............................................... 196Methylation-Independent Mechanisms of DNMT1 Depletion ......... 196Implications of Tumor DNA Methylation in Clinical Oncology ....... 197DNA Methylation: Diagnostics and Rationally DesignedCombination Therapy ................................................................... 197DNMT Inhibitors: The First of Many Epigenetic Therapeutics ........ 198Clinical Experience with Demethylating Agents for Cancer Therapy ... 198Antisense Cancer Therapy Targeting DNMT1 ................................. 198Clinical Development of MG98 ........................................................ 19915. Preclinical and Clinical Studies on 5-Aza-2'-Deoxycytidine,a Potent Inhibitor of DNA Methylation, in Cancer Therapy ............. 205Richard L. MomparlerHistorical Perspective ........................................................................ 205Pharmacology of 5-Aza-2'-Deoxycytidine (5-AZA) ........................... 206Evaluation of Antineoplastic Activity in Animal Models .................... 208Clinical Trials in Leukemia ............................................................... 209Clinical Trials in Tumors .................................................................. 210Future Perspectives on 5AZA in Cancer Therapy .............................. 21116. Anticancer Gene Therapy by in Vivo DNA Electrotransferof MBD2 Antisense............................................................................ 218Pascal Bigey and Daniel SchermanDelivery Principle .............................................................................. 219In Vivo DNA Electrotransfer: Targeted Tissues ................................ 220MBD2 Antisense Electrotransfer ....................................................... 224Epilogue ............................................................................................. 230Moshe SzyfIndex .................................................................................................. 235