1st Edition

Biomolecular Action of Ionizing Radiation

By Shirley Lehnert Copyright 2007
    560 Pages 4 Color & 174 B/W Illustrations
    by CRC Press

    562 Pages
    by CRC Press

    Embracing the transformation of radiation sciences by the recent surge of developments in molecular biology, this progressive text offers an up-to-date analysis of in vitro and in vivo molecular responses in the body induced by ionizing radiation. With a unique emphasis on medical physics applications, Biomolecular Action of Ionizing Radiation also presents a much needed, in-depth perspective on clinical applications for the treatment of cancer and radiation injuries.

    Based on a popular course given by the author at McGill University,the bookplaces the traditional tenets of radiation biology in the context of contemporary cell and molecular biology. Using terms that non-experts in molecular biology can understand, it clarifies the underlying mechanisms of radiation effects on molecular interactions including signal transduction pathways, modes of cell killing, and non-targeted effects. The author subsequently associates key principles and advances with potential applications, including the use of ionizing radiation as a cytotoxic and cytostatic agent, and radiosensitization by targeting molecular intermediates or signaling molecules involved in radiation-induced processes.

    Raising the standard for radiation biology texts that are currently available, Biomolecular Action of Ionizing Radiation is an outstanding resource for advanced undergraduate and graduate students in medical physics, radiation oncology, radiation biology, and those who have an interest in the radiation sciences and in cancer treatment.

    INTRODUCTION
    BASIC RADIATION PHYSICS AND CHEMISTRY
    Ionization and Excitation
    Types of Ionizing Radiation
    Electromagnetic Radiation
    Particulate Radiations
    Processes of Energy Absorption
    Direct and Indirect Action of Radiation
    Radiolysis of Water
    Haber–Weiss Reaction
    Reactions of the Primary Radiolytic Products of Water with Target Molecules
    Solute Radicals Form Stable Products
    Linear Energy Transfer
    Relative Biological Effectiveness
    BASIC CELL BIOLOGY AND MOLECULAR GENETICS
    Basic Cell Biology
    Cell Membrane
    Cytoplasm
    Nucleus
    Mitochondria
    Endoplasmic Reticulum and Ribosomes
    Golgi Complex
    Cytoskeleton
    Lysosomes
    Extracellular Materials
    Molecular Genetics
    DNA Structure
    DNA Structure Is the Basis for Heredity
    Mechanism of DNA Replication
    Transcribing DNA to RNA
    From RNA to Protein
    Proteins
    METHODS OF CELL AND MOLECULAR RADIOBIOLOGY
    Methods of Classical Radiobiology
    Cell Survival In Vitro: The Clonogenic Assay
    Non-Clonogenic Assays
    Methods of Cell Synchronization
    Determination of Duration of Phases of the Cell Cycle
    Measuring Cell Survival In Vivo
    Methods for Detecting Damage to DNA
    Strand Break Assays
    Measurement of DNA Damage and Repair in Individual Mammalian Cells
    Tools and Techniques of Molecular Biology
    Hybridization of Nucleic Acids
    Restriction Enzymes
    Gel Electrophoresis and Blotting Techniques
    Polymerase Chain Reaction
    Putting New Genes into Cells: DNA-Mediated Gene Transfer
    Generation of a Cloned Probe or DNA Library
    Sequencing of DNA
    Single Nucleotide Polymorphisms
    Functional Inactivation of Genes
    Genomic Methods of Tumor Analysis
    Analysis of Proteins
    Production of Monoclonal Antibodies
    Proteomics: Analysis of Protein Structure and Function
    Analysis of Tissue Sections and Single Cells
    Laser Capture Microdissection
    IONIZING RADIATION EFFECTS TO THE CYTOPLASM
    Oxidative Stress
    Metabolic Oxidative Stress
    Ionizing Radiation-Induced ROS/RNS
    Demonstration of Radiation-Induced Intracellular ROS/RNS
    Mechanisms of Generation and Amplification of ROS/RNS Following Irradiation of the Cytoplasm
    Consequences of Radiation-Induced Generation of ROS/RNS
    Effects of Ionizing Radiation on the Cell Membrane
    Structure of the Cell Membrane
    Lipid Peroxidation in Plasma Membranes
    Consequences of Damage to Plasma Membrane Lipids
    Plasma Membrane Is a Target for Ionizing Radiation-Induced Apoptosis
    DAMAGE TO DNA BY IONIZING RADIATION
    Mechanisms of DNA Damage: Physicochemical Relationships
    Mechanisms of Damage Induction: Chemical End Points
    Mechanisms of Damage Induction: Cellular End Points
    Types of DNA Damage
    Simple Damages to DNA: Base Damage and Single-Strand Breaks
    Apurinic or Apyrimidinic Sites
    Modifiers of Radiation Effect
    DNA Strand Breaks
    Double-Strand Breaks and Other Multiply Damaged Sites
    Distribution of MDS
    Clustered Damage in DNA of Mammalian Cells
    DNA-Protein Cross-Links
    REPAIR OF RADIATION DAMAGE TO DNA
    Overview of DNA Repair Mechanisms
    Repair of Radiation-Induced DNA Damage
    Repair of Base Damage and Single-Strand DNA Breaks: Base Excision Repair
    Role of PARP
    Processing of Multiply Damaged Sites by BER
    Repair of DNA Double-Strand Breaks
    Homologous Recombination
    Nonhomologous End Joining
    Genes and Proteins Involved in NHEJ
    Telomere-Bound Proteins and DNA Repair
    Human Syndromes Involving DNA Repair Deficiency
    Relationship between DNA Repair and Cell Survival
    CELLULAR RESPONSE TO DNA DAMAGE
    Passing on the Message that DNA Has Been Damaged
    Signal Transduction
    Signal Transduction Cascade Initiated by Radiation-Induced DNA Damage
    ATM Protein
    Functions of ATM
    How Does ATM Respond to Radiation-Induced DNA Damage?
    Role of ATM in DNA Repair
    ATM and the MRN Complex
    Tumor Suppressor Gene p53
    Turnover of p53: Mdm2
    Modulation of p53 Stability and Activity
    Radiation-Induced Growth Arrest
    Cell Cycle: Cyclins and Cyclin Dependent Kinases.
    Radiation-Induced Cell-Cycle Arrest
    Oncogenes and Cell-Cycle Checkpoints
    Variation in Radiosensitivity through the Cell Cycle
    P53-Mediated Apoptosis
    CHROMATIN STRUCTURE AND RADIATION SENSITIVITY
    Cell Nucleus
    Hierarchical Structure of Chromatin
    Structure and Function: Chromatin and the Nuclear Matrix
    Protection of DNA from Radiation Damage by Nuclear Proteins
    DNA-Protein Cross-Link Formation
    DSB Yields and RBE
    Role of Polyamines
    Radiation Sensitivity and the Stability of the DNA–Nuclear Matrix
    Radiosensitivity of Condensed Chromatin
    Role of Chromatin in DNA DSB Recognition and Repair
    Histone 2AX
    ATM Signaling from Chromatin
    Modulation of Chromatin Structure and Function by Acetylation
    Radiosensitization by Histone Deacetylase Inhibitors
    RADIATION-INDUCED CHROMOSOME DAMAGE
    DNA, Chromosomes, and the Cell Cycle
    Organization of DNA into Chromatin and Chromosomes
    Cell Cycle
    Mitosis
    Radiation-Induced Chromosome Aberrations
    Nature of the Initial Lesion
    Partial Catalog of Chromosome and Chromatid Aberrations
    Visualization of Chromosome Breaks during Interphase: Premature Chromosome Condensation
    FISH, mFISH, SKY, mBAND FISH, and Chromosome Painting
    Results of Whole Chromosome Painting
    Mechanisms of Aberration Formation
    Chromosome Localization and Proximity Effects
    Implications of Chromosome Damage
    Genetics
    Carcinogenesis
    Cell Survival, Dose Rate, and Fractionation Response
    Genomic Instability
    Biodosimetry and Risk Estimation
    MODULATION OF RADIATION RESPONSE VIA SIGNAL TRANSDUCTION PATHWAYS
    Intracellular Signaling
    Transmembrane Receptors
    ErbB Family of Receptor Kinases
    Cytoplasmic Signaling
    Ras Proto-Oncogene Family
    Signal Transduction Cascades
    Modulation of Radiation Response by Interaction of Signal Transduction Pathways
    Activation of ErbB Receptors by Ionizing Radiation
    Mechanism of Receptor Activation by Ionizing Radiation
    Role of Other Growth Factors
    Effects of Activation of GF Receptors on Cell Survival
    Autocrine Signaling
    Radiosensitization by Modulation of Signal Transduction Intermediates: Molecular Radiosensitizers
    ErbB Family Signal Inhibitors
    Clinical Applications of EGFR Signal Inhibitors
    Inhibition of the Ras-Mediated Signaling Pathway
    Clinical Application of Farnesyl Transferase Inhibitors
    Clinical Implications of Radiation-Induced Cell Signaling: Accelerated Cell Proliferation
    RADIATION-INDUCED APOPTOSIS
    Apoptosis
    Mechanisms of Apoptosis
    Caspases
    Apoptotic Signaling Pathways
    Intrinsic Apoptotic Signaling: The Mitochondrial Pathway
    Extrinsic Apoptotic Signaling
    Extrinsic Apoptotic Signaling Initiated at the Plasma Membrane: The Ceramide Pathway
    Why Do Some Cells Die as the Result of Apoptosis and Not Others?
    Apoptotic Processes and the In Vivo Radiation Response
    Normal Tissue
    Tumor Response
    EARLY AND LATE RESPONDING GENES INDUCED BY IONIZING RADIATION
    Gene Expression Is Induced by Ionizing Radiation
    Transcription Factors
    Important Transcription Factors Activated by Radiation
    Radiation-Gene Therapy
    Early and Late Response Genes
    Induction of Late Response Genes by Ionizing Radiation
    Cytokine-Mediated Responses in Irradiated Tissues
    Late Effects: Radiation-Mediated Fibrosis
    Gene Expression Associated with Radiation-Mediated Vascular Damage
    Cytokines as Therapeutic Agents: Radioprotection and Radiosensitization
    Radiosensitization
    Radioprotection
    Cytokines as Biomarkers of Radiation Exposure
    CELL DEATH, CELL SURVIVAL, AND ADAPTATION
    Cell Death
    Modes of Cell Death in Nonirradiated Cells
    Radiation-Induced Cell Death
    Role of p53
    Quantitating Cell Kill: Analysis of Cell Survival Curves
    Target Theory
    Linear Quadratic Model
    Lethal, Potentially Lethal Damage Model
    Repair Saturation Models
    Cell Survival at Low Radiation Doses
    Low Dose Hypersensitivity
    Adaptive Response
    Interactions of Adaptive Response and Bystander Effects
    Implications of Low Dose Effects for Risk Assessment
    Exposure to Background Radiation
    Adaptive Response and Neoplastic Transformation
    Clinical Implications of Low Dose Effects
    BYSTANDER EFFECTS AND GENOMIC INSTABILITY
    Dogma of Radiation Biology
    Bystander Effects
    Bystander Effects In Vitro
    Bystander Effects Seen after Transfer of Medium from Irradiated Cells
    Bystander Effects In Vivo
    Mechanisms Underlying Radiation-Induced Bystander Effects
    Implications in Risk Assessment
    Genomic Instability
    Genomic Instability In Vitro: Delayed Responses to Radiation Exposure
    Demonstration of Genomic Instability In Vivo
    Genomic Instability and Cancer
    Mechanisms Underlying Radiation-Induced Genomic Instability
    Relationship between Radiation-Induced Bystander Effects and Genomic Instability
    TUMOR RADIOBIOLOGY
    Tumor Radiobiology
    Unique Tumor Microenvironment
    Interstitial Fluid Pressure
    Tumor Hypoxia
    Tumor Acidosis
    Tumor Metabolism: Aerobic and Anaerobic Glycolysis
    Tumor Microenvironment Creates Barriers to Conventional Therapies
    Chemotherapy
    Radiotherapy
    Measurement of Tumor Hypoxia
    Radio-Sensitization by Modifying Tumor Oxygenation
    Effect of Hypoxia on Tumor Development and Progression
    Targeting the Ubiquitin/Proteasome System
    RADIATION BIOLOGY OF NONMAMMALIAN SPECIES: THREE EUKARYOTES AND A BACTERIUM
    Introduction: Lower Eukaryotes in Radiation Research
    Yeast, a Single-Celled Eukaryote
    Radiation Biology of Yeast
    Radiosensitive Mutants for the Study of DNA Repair
    DNA Damage Checkpoints
    Genome Wide-Screening for Radiation Response-Associated in Yeast
    Caenorhabditis elegans
    Apoptosis in C. elegans
    Cell Cycle Checkpoints in C. elegans
    DNA Repair in Celegans
    DNA Damage Responses in C. elegans
    Radiation-Induced Mutation
    Worms in Space
    Zebrafish
    Zebrafish for the Evaluation of Genotoxic Stress
    Effects of Ionizing Radiation on Brain and Eye Development
    Modulation of Radiation Response
    Gene Function during Embryonic Development
    Hematological Studies with Zebra Fish
    Deinococcus radiodurans
    Origins of Extremophiles
    Genetics of D. radiodurans
    Characteristics of D. radiodurans Predisposing to Radiation Resistance
    Regulation of Cellular Responses to Extensive Radiation Damage
    Double-Strand Break Tolerance
    An Economic Niche for D. radiodurans
    References
    Glossary
    Index
    * Each Chapter contains a Summary section and References

    Biography

    Shirley Lehnert

    "… The new textbook is targeted at students in radiation oncology and medical physics and should be a useful resource for graduate students with interests in radiation sciences and cancer treatment. … Overall, I felt the author has generally achieved the aim of developing a textbook on applications of molecular biology to radiation biology relating to radiation oncology. …"
    Crystallography Reviews, Vol. 15, No. 2, April-June 2009

    "The major strength of this book likes in its in-depth coverage of recent advances in radiation-induced signal transduction pathways and molecular mechanisms of cellular responses to ionizing radiation . . . succeeded in providing an up-to-date synopsis of the field of radiation research in the early 21st century and is a worthy addition to the library of didactic textbooks in our field. This book has a comprehensive and clearly laid out table of contents. The text is succinct and easy to read. This book certainly belongs on the bookshelf of anyone who is interested in understanding radiation biology including residents, graduate students, and postdoctoral researchers. In particular, radiation oncology residents will find this book to be an excellent source of information for understanding the molecular basis of radiation biology."

    – Zhong Yun and Joann B. Sweasy, Department of Therapeutic Radiology, Yale University School of Medicine, 2009

    ". . . this progressive text offers an up-to-date analysis of in vitro and in vivo molecular responses in the body induced by ionizing radiation. With a unique emphasis on medical physics applications, this volume also presents a much needed, in-depth perspective on clinical applications for the treatment of cancer and radiation injuries . . . an outstanding resource for advanced undergraduate and graduate students in medical physics, radiation oncology, radiation biology, and those who have an interest in the radiation sciences and in cancer treatment."

    –In Anticancer Research, Nov-Dec 2008, Vol. 28, No. 6B