The Molecular Theory of Radiation Biology

ISBN-13: 9783642815218 / Angielski / Miękka / 2012 / 377 str.

K. H. Chadwick; H. P. Leenhouts; K. H. Chadwick

Opis

In late 1971 we were involved in a study of the interaction of radiation with matter and were trying to use measurements of radiation fluorescence in biological molecules to indicate how radiation affected living cells. It soon became apparent that we were working in the dark; the doses we used to get a significant signal were too large to be of interest for radiation biology and although the DNA molecule appeared to be the most likely target molecule we did not know which sort of events and which sort oflesions were the most important. We decided to alter our approach to see if we could find any consistent mathematical order in the radiobiological dose relationships. We found that cell survival curves could be very usefully described by a linear-quadratic dose relationship and very soon came to the somewhat premature but, as it turned out, most effective conclusion that the induction of DNA double strand breaks should be linear-quadratic. In deciding that the DNA double strand break was the crucial and all-important lesion we were able to associate the mathematical analysis with the biology of the cell and were able to relate known properties of the DNA molecule to known radiobiological effects. On the other hand, we were restricted and brought, from an abstract two-hit lesion which could have any property one wished, down to earth, to a defined moleccular structure of nanometer dimensions and well-known functions and properties.

Spis treści

1. Quantitative Radiation Biology.- 1.1 Radiation in Society.- 1.2 Radiation Biology: the Interdisciplinary Discipline.- 1.3 The Importance of Cellular Biology.- 1.4 The Quantitative Analysis of Radiation Action: a Brief Historical Review.- 1.5 Desiderata for a Quantitative Theory of Radiation Biology.- 2. The DNA Molecule and Its Role in the Cell.- 2.1 Introduction.- 2.2 The Structure and Dimensions of the DNA Molecule.- 2.3 Base Sequences and the Genetic Code.- 2.4 DNA Replication.- 2.5 DNA in Chromosomes.- 2.6 The Diploid Cell, Mitosis and Meiosis.- 2.7 Radiation-Induced Damage to DNA.- 2.7.1 DNA Base Damage.- 2.7.2 DNA Single Strand Breaks.- 2.7.3 DNA Double Strand Breaks.- 3. The Molecular Model for Cell Survival Following Radiation.- 3.1 Historical Development.- 3.2 The Philosophical Framework of the Model.- 3.3 The Induction of DNA Double Strand Breaks by Radiation.- 3.3.1 The Induction of DNA Single Strand Breaks.- 3.3.2 The Induction of DNA Double Strand Breaks in One Radiation Event.- 3.3.3 The Induction of DNA Double Strand Breaks in Two Radiation Events.- 3.3.4 The Total Induction of DNA Double Strand Breaks.- 3.3.5 The Induction of DNA Double Strand Breaks with Repair.- 3.3.6 The Influence of Base Damage on the Production of Double Strand Breaks.- 3.4 The Relationship Between Cell Survival and DNA Double Strand Breaks.- 3.5 The Cell Survival Curve.- 3.5.1 Cell Survival as Critérium.- 3.5.2 Correction for Cell Multiplicity.- 3.5.3 The Shape of the Cell Survival Curve.- 3.5.4 The Analysis of Experimental Data.- 3.6 Variation in the Survival Curve Through the Cell Cycle.- 3.7 Asynchronous Cell Populations.- 3.8 The Experimental Correlation Between Cell Survival and DNA Double Strand Breaks.- 3.9 Summary.- 4. Chromosomal Aberrations.- 4.1 Introduction.- 4.2 The Nature and Yield of Chromosomal Aberrations.- 4.3 The Classical and Exchange Theories of Radiation- Induced Chromosomal Aberrations.- 4.3.1 The Classical Theory.- 4.3.2 The Exchange Theory.- 4.3.3 The Problem.- 4.4 The Molecular Theory of Radiation-Induced Chromosomal Aberrations.- 4.4.1 The Yield of Chromosomal Aberrations.- 4.4.2 The Formation of Chromosomal Aberrations by the Process of Telomere-Break Rejoining.- 4.4.2.1 A Possible Molecular Mechanism for Rejoining Between a Telomere and a Break and the Stabilization of a Broken End.- 4.4.3 The Formation of Chromosomal Aberrations by the Process of Recombinational Rejoining.- 4.4.3.1 Repetitive DNA.- 4.4.3.2 Palindromes.- 4.4.3.3 Incompleteness.- 4.4.4 The Experimental Evidence for Telomere-Break Rejoining.- 4.4.4.1 The Haplopappus Experiment.- 4.4.4.2 Other Radiation Experiments.- 4.4.4.3 Medical Cytology.- 4.4.5 The Experimental Evidence for the Process of Recip¬rocal Recombination.- 4.4.6 Two Mechanisms for the Formation of Chromosomal Aberrations?.- 4.4.6.1 The Molecular Nature of the Telomere.- 4.4.6.2 The Role of Caffeine.- 4.5 Complex Chromosomal Rearrangements.- 4.6 Gene Transplantation.- 4.7 Summary.- 5. Somatic Mutations.- 5.1 Point and Chromosome Mutations.- 5.2 Some Molecular Mechanisms Which Could Give Rise to Mutations from DNA Double Strand Breaks.- 5.2.1 The Rejoining of Single Stranded Tails.- 5.2.2 Resnick’s Model for Gene Conversion.- 5.2.3 Resnick’s Model for Reciprocal Recombination.- 5.2.4 Rejoining Between a Telomere and a Single Stranded Tail.- 5.2.5 No Repair.- 5.2.6 The Repair Processes and Mutation Induction.- 5.3 Mutation Frequency Dose Relationships.- 5.3.1 The Induction of Mutations.- 5.3.2 The Suppression of Mutation Expression.- 5.3.3 The Influence of Cell Killing.- 5.4 The Analysis of Experimental Data.- 5.5 Two Mutations in the Same Cell Population.- 5.6 The Mutation Spectrum.- 5.7 Summary.- 6. Correlations.- 6.1 Introduction.- 6.2 The Survival-Survival Correlation.- 6.3 The Survival-Chromosomal Aberration Correlation.- 6.4 The Correlation Between Different Chromosomal Aberrations.- 6.5 The Correlation Between “Normal” Chromosomal Aberrations and “Complex” Chromosomal Aberrations.- 6.6 The Correlation Between Survival and Somatic Mutation.- 6.7 The Correlation Between Two Different Mutations Induced in the Same Cell Population.- 6.8 The Peak Incidence - an Implied Correlation.- 6.9 What Do the Correlations Mean?.- 7. Repair.- 7.1 Introduction.- 7.2 The Repair of DNA Single Strand Breaks and the Dose Rate Effect.- 7.2.1 Experimental Evidence on DNA Single Strand Break Repair.- 7.2.2 The Time Scale of the Three Dose Rate Regions.- 7.2.3 The Exponential Repair of DNA Single Strand Breaks and Its Effect on the Dose Response Relationships.- 7.2.4 Implications for the InS/D Versus D Analysis.- 7.2.5 Complicated Repair Rates.- 7.2.6 Practical Difficulties in the Determination of Dose-rate Effects.- 7.3 The Repair of DNA Single Strand Breaks and the Effect of Dose Fractionation.- 7.3.1 The Analysis of Repair Using Fractionation Studies.- 7.4 The Repair of DNA Double Strand Breaks and the Post-Irradiation Effect.- 7.4.1 The Quantitative Effect of DNA Double Strand Break Repair on Cell Survival.- 7.4.1.1 The Time Dependence of the Repair of DNA Double Strand Breaks.- 7.4.2 The Quantitative Effect of DNA Double Strand Break Repair on Chromosomal Aberration Yield.- 7.4.3 The Quantitative Effect of DNA Double Strand Break Repair on Mutation Frequency.- 7.4.4 Is the Efficiency for the Repair of DNA Double Strand Breaks Always Dose-independent?.- 7.5 The Difference Between Sub-lethal Damage Repair and Potentially Lethal Damage Repair.- 8. Radiation Quality.- 8.1 The Differing Shape of Dose-response Relationships.- 8.2 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.3 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.4 How Constant is the Value of RBEo?.- 8.4.1 The Variation of RBEo in the Cell Cycle.- 8.4.2 The Effect of Different Conditions in the Cell.- 8.4.3 Extremely High Values of RBEo.- 8.5 The Size of the Target.- 8.6 A Calculation of the Dependence of the a- and ß- Coefficients on Radiation Quality.- 8.6.1 The Track Model.- 8.6.2 A Calculation of the Induction of DNA Single and Double Strand Breaks.- 8.6.3 A Quantitative Assessment of the Dependence of Cell Survival on Radiation Quality.- 8.6.4 The Relation Between Physics, Chemistry, and Biology.- 8.7 Summary.- 9. Cancer.- 9.1 Introduction.- 9.2 Somatic Mutation and Cancer.- 9.2.1 Historical Development.- 9.2.2 The Modern Evidence Supporting the Somatic Mutation Theory.- 9.2.2.1 The Mutagen Screening Tests.- 9.2.2.2 The Typical Chromosomal Aberrations.- 9.2.2.3 The Repair-deficient Human Disorders.- 9.3 The Malignant Cell.- 9.4 Radiation-Induced Cell Transformation.- 9.4.1 The Diploid Carrier Cell.- 9.4.2 The Tetraploid Carrier Cell.- 9.4.3 The Diploid Non-Carrier Cell.- 9.5 Extrapolation to Animals and Man.- 9.5.1 Experimental Data for Animals.- 9.5.2 Radiation-induced Malignancy in Man.- 9.5.2.1 Sparsely Ionizing Radiation.- 9.5.2.2 Densely Ionizing Radiation.- 9.6 Conclusion.- 10. Genetic Effects.- 10.1 Introduction.- 10.2 The Induction of Dominant Lethal Mutations.- 10.3 Correlations Between Different Genetic End Points.- 10.3.1 The Correlation Between Dominant Lethality and the Yield of Chromosomal Aberrations.- 10.3.2 The Correlation Between Different Chromosomal Aberrations.- 10.3.3 The Correlation Between Dominant Visible Mutations and Specific Locus Mutations in the Mouse.- 10.3.4 The Correlation Between Dominant and Recessive Lethal Mutations.- 10.4 The Induction of Translocations in the Spermatogonia of the Mouse.- 10.4.1 The Spermatogonial Stem Cell Development.- 10.4.2 Acute Irradiation.- 10.4.3 The Effect of Dose Rate.- 10.4.4 Short-Term Fractionation.- 10.4.5 Twenty-Four-Hour Fractionation.- 10.4.6 Long-Term Fractionation.- 10.5 The Induction of Specific Locus Mutations in the Mouse.- 10.6 Conclusions.- 11. Synergistic Interaction.- 11.1 Introduction.- 11.2 Theoretical Development.- 11.3 Agent Toxicity.- 11.4 Agent Dosimetry.- 11.5 Experimental Examples of Synergism.- 11.5.1 The Interaction of Radiation with UV.- 11.5.2 The Interaction of Radiation with Halogenated Pyrimidine Analogues.- 11.5.3 The Interaction of Radiation with Nitrosourea Compounds.- 11.5.4 The Interaction of Radiation with Diamide.- 11.6 General Discussion.- 12. Implications.- 12.1 Radiological Protection.- 12.1.1 Sparsely Ionizing Radiation.- 12.1.2 Densely Ionizing Radiation.- 12.1.3 Cancer as a Recessive Genetic Character.- 12.1.4 Genetic Effects.- 12.1.5 The Effect of Environmental Mutagens.- 12.2 The Chemical Hazard.- 12.3 Radiation Therapy.- 12.3.1 Fractionation.- 12.3.1.1 ?-Type Sensitizer.- 12.3.1.2 ?-Type Sensitizer.- 12.3.1.3 Implications for the Choice of Sensitizer.- 12.4 Plant Mutation Breeding.- 12.5 Postscript.- References.- List of Abbreviations.