DNA Repair in Cancer Therapy

DNA Repair in Cancer Therapy

Molecular Targets and Clinical Applications

2nd Edition - June 7, 2016

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  • Editors: Mark Kelley, Melissa Fishel
  • eBook ISBN: 9780128035993
  • Hardcover ISBN: 9780128035825

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DNA Repair and Cancer Therapy: Molecular Targets and Clinical Applications, Second Edition provides a comprehensive and timely reference that focuses on the translational and clinical use of DNA repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. Experts on DNA repair proteins from all areas of cancer biology research take readers from bench research to new therapeutic approaches. This book provides a detailed discussion of combination therapies, in other words, how the inhibition of repair pathways can be coupled with chemotherapy, radiation, or DNA damaging drugs. Newer areas in this edition include the role of DNA repair in chemotherapy induced peripheral neuropathy, radiation DNA damage, Fanconi anemia cross-link repair, translesion DNA polymerases, BRCA1-BRCA2 pathway for HR and synthetic lethality, and mechanisms of resistance to clinical PARP inhibitors.

Key Features

  • Provides a comprehensive overview of the basic and translational research in DNA repair as a cancer therapeutic target
  • Includes timely updates from the earlier edition, including Fanconi Anemia cross-link repair, translesion DNA polymerases, chemotherapy induced peripheral neuropathy, and many other new areas within DNA repair and cancer therapy
  • Saves academic, medical, and pharma researchers time by allowing them to quickly access the very latest details on DNA repair and cancer therapy
  • Assists researchers and research clinicians in understanding the importance of the breakthroughs that are contributing to advances in disease-specific research


Basic science and translational cancer researchers, geneticists, clinical geneticists, oncologists, radiation oncologists, cell biologists, pharmaceutical scientists, toxicologists, others interested in DNA repair in cancer therapy

Table of Contents

    • List of Contributors
    • Preface
    • Acknowledgments
    • Chapter 1: Overview of DNA repair pathways, current targets, and clinical trials bench to clinic
      • Abstract
      • Introduction
      • Overview of DNA Repair Pathways
      • MGMT Inhibition: First Foray Into DNA Repair Inhibition
      • PARP: The Archetypical Inhibitor
      • Synthetic Lethality: Targeting a Cell That is Already Genetically Unstable
      • DNA Damage Checkpoints
      • Inhibitors in Development
      • Future Perspectives
      • Acknowledgments
    • Chapter 2: MGMT—a critical DNA repair gene target for chemotherapy resistance
      • Abstract
      • Cell Death Pathways Triggered by O6-Alkylating Anticancer Drugs
      • Repair of O6-Alkylated DNA by MGMT
      • Regulation of MGMT
      • Expression of MGMT in Normal and Malignant Cells
      • MGMT as Prognostic/Predicting Factor in Cancer Therapy
      • MGMT Polymorphisms in Cancer Therapy
      • Targeting MGMT in Cancer Therapy
      • Conclusions
    • Chapter 3: Understanding the basics for translating the base excision repair pathway from benchtop to bedside in cancer treatment
      • Abstract
      • Base Excision Repair: A Pathway for Small Lesions Having Big Consequences for Cancer Cells
      • Central Role of APE1 in BER and Its Relevance to Cancer Biology
      • The APE1/NPM1 Interaction in Cancer
      • BER as a Promising Target to Improve Cancer Therapy
      • Acknowledgments
    • Chapter 4: The role of PARP in DNA repair and its therapeutic exploitation
      • Abstract
      • Introduction
      • Poly(ADP-ribose) Polymerases
      • Preclinical Data Supporting Clinical Development of PARP Inhibitors
      • Potentiation of the Cytotoxicity on DNA Damaging Chemotherapy Agents
      • Single Agent Activity of PARP Inhibitors
      • Potentiation of the Cytotoxicity of Radiotherapy
      • PARP Trapping—A Novel Mechanism of PARP Inhibitors
      • Clinical Development of PARP Inhibitors
      • First Clinical Trial
      • Chemotherapy Combination Studies
      • Synthetic Lethality in HR Deficiency
      • Single-Agent Data Leading to License of Olaparib
      • Biomarker Refinement to Identify Patients With HRD Tumors
      • Clinical Trials Identifying HRD Predictive Biomarkers
      • Wider Potential Applications of PARPi
      • Summary and Future Directions
    • Chapter 5: Targeting the nucleotide excision repair pathway for therapeutic applications
      • Abstract
      • The Nucleotide Excision Repair Pathway
      • Targeting NER in Combination with DNA Damaging Chemotherapy
      • Targeting ERCC1/XPF
      • Targeting DNA Damage Recognition and Verification via XPA
      • Targeting the Multifunctional RPA DNA-Binding Protein
      • Alternative Mechanisms of NER Inhibition
      • Conclusions and Perspective for the Future
    • Chapter 6: The DNA mismatch repair pathway
      • Abstract
      • The Canonical MMR Pathway
      • Mitochondrial Mismatch Repair
      • Treating DNA Repair Deficient Cancers
      • New Ways to Treat DNA Mismatch Repair Deficient Cancers
      • Conclusions
    • Chapter 7: Chemotherapeutic intervention by inhibiting DNA polymerases
      • Abstract
      • The Impact of Chemotherapeutic Agents on DNA Synthesis
      • DNA Polymerases
      • Classification of DNA Polymerases
      • Structural Features of DNA Polymerases
      • Kinetic and Chemical Mechanisms of DNA Polymerization
      • Exonuclease Proofreading
      • Effects of DNA-Damaging Agents on DNA Polymerization
      • The Role of DNA Polymerases in DNA Repair
      • General Strategies to Inhibit DNA Polymerase Activity
      • Clinical Utility of Purine Nucleoside Analogs
      • Pharmacokinetic Features of Purine Nucleoside Analogs
      • Biochemical Mechanism of Action
      • Other Cytotoxic Mechanisms of Fludarabine
      • Clinical Activity of Fludarabine as a Monotherapeutic Agent
      • Clinical and Biochemical Studies of Fludarabine Combined with DNA-Damaging Agents
      • Other Purine Nucleoside Analogs
      • Clinical Utility of Pyrimidine Nucleoside Analogs
      • Pharmacokinetic Properties of Pyrimidine Nucleosides
      • Mechanism of Action
      • Clinical Utility of Gemcitabine as a Monotherapeutic Agent
      • Clinical and Biochemical Studies of Gemcitabine Combined with DNA-Damaging Agents
      • Potential Mechanisms for Synergistic Activity
      • Nucleoside Analogs as Radiosensitizers
      • Clinical Complications Associated with Nucleoside Analogs
      • Emerging Areas in Chemotherapeutic Intervention
    • Chapter 8: Targeting homologous recombination repair in cancer
      • Abstract
      • Mechanisms and Regulation of Homologous Recombination Repair
      • Conclusions
      • Homologous Recombination Repair and Cancer
      • Strategies for Targeting Homologous Recombination Repair in Cancer
      • Conclusions
      • Acknowledgments
      • List of acronyms and abbreviations
      • Glossary
    • Chapter 9: DNA double-strand repair by nonhomologous end joining and its clinical relevance
      • Abstract
      • Introduction
      • Canonical NHEJ
      • Noncanonical NHEJ
      • Opportunities for Therapeutic Targeting
      • Conclusions
    • Chapter 10: Diversity and implication of MAPK signal transduction involved in the regulation of chemotherapy-induced DNA damage response
      • Abstract
      • Introduction
      • Growth Factor Receptor-Coupled Signal Transduction Pathways That Are Points of Convergence for DNA Damage Response and DNA Repair
      • Signal Transduction Pathways That Regulate Effectors of the DNA-Damage Response
      • Kinases Involved in Phosphorylation of DNA Repair Proteins
      • Histone Modifiers Implicated in the Regulation of DNA Damage Response and DNA Repair
      • Targeting the MAPK Signal Transduction Pathways for Modulation of Chemotherapy-Induced DNA Damage and Therapeutic Response
      • Concluding Remarks and Perspectives
      • Acknowledgments
      • List of Acronyms and Abbreviations
    • Chapter 11: Radiation DNA damage and use in cancer/therapeutics-translation of radiation modifiers
      • Abstract
      • Introduction
      • Induction and Repair of DNA Damage
      • Radiotherapy
      • Targeting
      • Prediction
      • Conclusions
    • Chapter 12: The FANCA to FANCZ of DNA interstrand crosslink repair: Lessons from Fanconi anemia
      • Abstract
      • Introduction
      • Fanconi Anemia: Disease and Diagnosis
      • Fanconi Anemia: Genetics and Phylogeny
      • FA/BRCA ICL Repair Pathway
      • Sensing ICL
      • Signaling ICL via the FA Core Complex
      • What Does Ubiquitination Do To FANCD2 and FANCI?
      • Deubiquitination of FANCI:FANCD2 During ICL Repair
      • Unloading CMG Helicase and Strand Cleavage
      • Homologous Recombination Repair, Translesion Synthesis, and Completion of Replication
      • Cell Cycle Effects Post ICL Damage, Link to FA
      • ICLs and Chemotherapy
      • Side-Effects in Clinical Use of ICL Generating Agents
      • ICLs as Cancer Causing Agents
      • Increasing the Efficacy of ICL Inducing Agents
      • Increasing Efficacy of ICL Damage by Protecting Normal Cells
      • Conclusions
    • Chapter 13: The role of DNA damage and repair in toxicity to postmitotic cells caused by cancer therapies
      • Abstract
      • Introduction
      • Cancer Therapy-Induced Neurotoxicity
      • Cancer Therapy-Induced Cardiotoxicity
      • Cancer Therapy-Induced Toxicity to Skeletal Muscle
      • DNA Damage and Repair in Neurons
      • DNA Damage and Repair in Cardiac Muscle
      • DNA Damage and Repair in Skeletal Muscle
      • DNA Damage and Repair Alter Toxicity Induced by Cancer Therapies
      • Summary
    • Subject Index

Product details

  • No. of pages: 464
  • Language: English
  • Copyright: © Academic Press 2016
  • Published: June 7, 2016
  • Imprint: Academic Press
  • eBook ISBN: 9780128035993
  • Hardcover ISBN: 9780128035825

About the Editors

Mark Kelley

Mark R. Kelley, PhD is currently the Betty and Earl Herr Chair in Pediatric Oncology Research, Associate Director for the Herman B Wells Center for Pediatric Research, and the Associate Director of Basic Science Research at the IU Simon Cancer Center. Dr. Kelley’s laboratory studies DNA base excision repair in normal and tumor cells, including the study of DNA repair genes in cognitive dysfunction and peripheral neuropathy. He holds 10 patents related to the use of DNA repair targets for cancer therapy and serves on the consulting and scientific boards of several companies. Thus far Dr. Kelley’s research resulted in over 160 articles published in peer reviewed journals along with numerous reviews and book chapters.

Affiliations and Expertise

Betty and Earl Herr Chair in Pediatric Oncology Research; Associate Director, Herman B. Wells Center for Pediatric Research; Associate Director for Basic Science Research, Simon Cancer Center, Indiana University School of Medicine; Professor, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA

Melissa Fishel

Dr. Fishel is a DNA repair expert who is highly published and is at the forefront in the development of new tumor models focusing on DNA repair pathways in cancer.

Affiliations and Expertise

Assistant Research Professor of Pediatric Oncology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

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