Showing papers in "Radiation Research in 1996"
TL;DR: This continues the series of periodic general reports on cancer mortality in the cohort of A-bomb survivors followed by the Radiation Effects Research Foundation, and analysis includes an additional 10,500 survivors with recently estimated radiation doses.
Abstract: This continues the series of periodic general reports on cancer mortality in the cohort of A-bomb survivors followed by the Radiation Effects Research Foundation. The follow-up is extended by the 5 years 1986–1990, and analysis includes an additional 10,500 survivors with recently estimated radiation doses. Together these extensions add about 550,000 person-years of follow-up. The cohort analyzed consists of 86,572 subjects, of which about 60% have dose estimates of at least 0.005 Sv. During 1950–1990 there have been 3086 and 4741 cancer deaths for the less than and greater than 0.005 Sv groups, respectively. It is estimated that among these there have been approximately 420 excess cancer deaths during 1950–1990, of which about 85 were due to leukemia. For cancers other than leukemia (solid cancers), about 25% of the excess deaths in 1950–1990 occurred during the last 5 years; for those exposed as children this figure is nearly 50%. For leukemia only about 3% of the excess deaths in 1950–1990 occurred in ...
914 citations
TL;DR: This presentation discusses the role of catalytic metals in free radical-mediated oxidations, ascorbate as both a pro-oxidant and an antioxidant, use of asCorbate to determine adventitious catalytic metal concentrations, and uses of ascorBate radical as a marker of oxidative stress.
Abstract: Trace levels of transition metals can participate in the metal-catalyzed Haber-Weiss reaction (superoxide-driven Fenton reaction) as well as catalyze the oxidation of ascorbate. Generally ascorbate is thought of as an excellent reducing agent; it is able to serve as a donor antioxidant in free radical-mediated oxidation processes. However, as a reducing agent it is also able to reduce redox-active metals such as copper and iron, thereby increasing the pro-oxidant chemistry of these metals. Thus ascorbate can serve as both a pro-oxidant and an antioxidant. In general, at low ascorbate concentrations, ascorbate is prone to be a pro-oxidant, and at high concentrations, it will tend to be an antioxidant. Hence there is a crossover effect. We propose that the "position" of this crossover effect is a function of the catalytic metal concentration. In this presentation, we discuss: (1) the role of catalytic metals in free radical-mediated oxidations; (2) ascorbate as both a pro-oxidant and an antioxidant; (3) catalytic metal catalysis of ascorbate oxidation; (4) use of ascorbate to determine adventitious catalytic metal concentrations; (5) use of ascorbate radical as a marker of oxidative stress; and (6) use of ascorbate and iron as free radical pro-oxidants in photodynamic therapy of cancer.
851 citations
TL;DR: Questions concerning the involvement of free hydroxyl radicals or reactions of metal/oxo intermediates may obscure a wider appreciation of the importance of Fenton chemistry involving hypohalous acids rather than hydrogen peroxide as the oxidant.
Abstract: In 1876, Fenton described a colored product obtained on mixing tartaric acid with hydrogen peroxide and a low concentration of a ferrous salt. Full papers in 1894 and 1896 showed the product was dihydroxymaleic acid. Haber, Weiss and Willstatter proposed in 1932-1934 the involvement of free hydroxyl radicals in the iron(II)/hydrogen peroxide system, and Baxendale and colleagues around 1950 suggested that superoxide reduces the iron(III) formed on reaction, explaining the catalytic nature of the metal. Since Fridovich and colleagues discovered the importance of superoxide dismutase in 1968, numerous studies have sought to explain the deleterious effects of cellular oxidative stress in terms of superoxide-driven Fenton chemistry. There remain questions concerning the involvement of free hydroxyl radicals or reactions of metal/oxo intermediates. However, these outstanding questions may obscure a wider appreciation of the importance of Fenton chemistry involving hypohalous acids rather than hydrogen peroxide as the oxidant.
528 citations
TL;DR: This review summarizes the current status of knowledge about radiation-induced genomic instability and discusses events and processes likely to be involved in the initiation and perpetuation of the unstable phenotype, the potential role of epigenetic factors in influencing the onset of genomic instability, and the delayed effects of cellular exposure to ionizing radiation.
Abstract: Genomic instability is characterized by the increased rate of acquisition of alterations in the mammalian genome. These changes encompass a diverse set of biological end points including karyotypic abnormalities, gene mutation and amplification, cellular transformation, clonal heterogeneity and delayed reproductive cell death. The loss of stability of the genome is becoming accepted as one of the most important aspects of carcinogenesis, and the numerous genetic changes associated with the cancer cell implicate genomic stability as contributing to the neoplastic phenotype. Multiple metabolic pathways govern the accurate duplication and distribution of DNA to progeny cells; other pathways maintain the integrity of the information encoded by DNA and regulate the expression of genes during growth and development. For each of these functions, there is a normal baseline frequency at which errors occur, leading to spontaneous mutations and other genomic anomalies. This review summarizes the current status of knowledge about radiation-induced genomic instability. Those events and processes likely to be involved in the initiation and perpetuation of the unstable phenotype, the potential role of epigenetic factors in influencing the onset of genomic instability, and the delayed effects of cellular exposure to ionizing radiation are discussed.
456 citations
TL;DR: Results obtained with normal human cells are similar to those of other investigators who observed excessive SCEs in immortalized rodent cells beyond that which could be attributed exclusively to nuclear traversals by alpha particles, and point to the existence of an alternative, extranuclear target through which alpha particles cause DNA damage, as detected by SCE analysis.
Abstract: Deshpande, A., Goodwin, E. H., Bailey, S. M., Marrone, B. L. and Lehnert, B. E. Alpha-Particle-Induced Sister Chromatid Exchange in Normal Human Lung Fibroblasts: Evidence for an Extranuclear Target. Radiat. Res. 145,260-267 (1996). We investigated the relationship between nuclear hits by a particles and the subsequent occurrence of sister chromatid exchanges (SCEs) in normal human diploid lung fibroblasts (HFLl). Cells were exposed to 'j8pu a particles at doses ranging from 0.4-12.9 cGy and subsequently analyzed for SCEs. A significant increase in SCE frequency was observed even at the lowest dose examined. The extent of induction of SCEs in the HFLl cells showed dose dependency in the very low dose range, i.e. 0.4-2.0 cGy. Thereafter, induction of SCEs was independent of dose. Based on measurements of the nuclear areas of the HFLl cells in conjunction with target theory calculations, the lowest dose resulted in an -8.6-fold increase in the percentage of cells showing excessive SCEs over the theoretically expected percentage of cells whose nuclei were calculated to be traversed by one or more a particles. The extent of the discrepancies between theoretically expected and experimentally observed frequencies of SCEs became progressively reduced with increasing radiation dose. We additionally determined that SCEs induced by the a particles have no significant dependency on the time of cell collection after exposure to a selected dose of a particles, thereby confirming that the differences between the theoretically predicted and observed SCE frequencies were not due to an artifact of the time of cell sampling for the SCE measurements. These results obtained with normal human cells are similar to those of other investigators who observed excessive SCEs in immortalized rodent cells beyond that which could be attributed exclusively to nuclear traversals by a particles. Such consistent findings point to the existence of an alternative, extranuclear target through which a particles cause DNA damage, as detected by SCE analysis. The existence of an extranuclear compartment as a target for a particles may have important implications for the susceptibility of lung cells to the DNA-damaging effects of a-particle exposure due to the inhalation of radon progeny. o 1996 by Radiation Research Societj
286 citations
TL;DR: The results demonstrate that low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation, and suggest that a single low dose, at background or occupational exposure levels, may in some circumstances reduce rather than increase cancer risk.
Abstract: We have previously shown that chronic exposure of plateau-phase C3H 10 T1/2 cells to (60)Co gamma radiation at doses as low as 10 cGy protected the cells against neoplastic transformation by a subsequent large acute radiation exposure. We have also shown that this induced resistance to neoplastic transformation correlated with an increased ability to repair radiation-induced chromosome breaks. We now show that a single exposure of quiescent cells to doses as low as 0.1 cGy also reduces the risk of neoplastic transformation, from the spontaneous level to a rate three- to fourfold below that level. Higher doses, up to 10 cGy at the same dose rate (0.24 cGy/min), did not reduce the neoplastic transformation frequency further. This protective effect was seen only in irradiated cells that were allowed to incubate at 37 degrees C before release from contact inhibition. Cells released into low-density subcultures immediately after irradiation had unchanged neoplastic transformation frequencies. These results demonstrate that low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation. If similar processes are induced in human cells, the results also suggest that a single low dose, at background or occupational exposure levels, may in some circumstances reduce rather than increase cancer risk, a conclusion inconsistent with the linear no-threshold model of cancer risk from radiation.
284 citations
TL;DR: Results are shown that these results are in good agreement with theoretical calculations based on treating the 30-nm chromatin fiber as the target for ionizing particles, and it is proposed that such clusters be designated "regionally multiply damaged sites."
Abstract: The basic 30-nm chromatin fiber in the mammalian cell consists of an unknown (possibly helical) arrangement of nucleosomes, with about 1.2 kb of DNA per 10-nm length of fiber. Track-structure considerations suggest that interactions of single delta rays or high-LET particles with the chromatin fiber might result in the formation of multiple lesions spread over a few kilobases of DNA (see the accompanying paper: W.R. Holley and A. Chatterjee, Radiat. Res. 145, 188-199, 1996). In particular, multiple DNA double-strand breaks and single-strand breaks may form. To test this experimentally, primary human fibroblasts were labeled with [3H]thymidine and exposed at 0 degrees C to X rays or accelerated nitrogen or iron ions in the LET range of 97-440 keV/microns. DNA was isolated inside agarose plugs and subjected to agarose gel electrophoresis under conditions that allowed good separation of 0.1-2 kb size DNA. The bulk of DNA remained in the well or migrated only a small distance into the gel. It was found that DNA fragments in the expected size range were formed linearly with dose with an efficiency that increased with LET. A comparison of the yield of such fragments with the yield of total DNA double-strand breaks suggests that for the high-LET ions a substantial proportion (20-90%) of DNA double-strand breaks are accompanied within 0.1-2 kb by at least one additional DNA double-strand break. It is shown that these results are in good agreement with theoretical calculations based on treating the 30-nm chromatin fiber as the target for ionizing particles. Theoretical considerations also predict that the clusters will contain numerous single-strand breaks and base damages. It is proposed that such clusters be designated "regionally multiply damaged sites." Postirradiation incubation at 37 degrees C resulted in a decline in the number of short DNA fragments, suggesting a repair activity. The biological significance of regionally multiply damaged sites is presently unknown.
235 citations
220 citations
TL;DR: The temporal relationship between the elevation of these cytokines and the strain-dependent variation in fibrosis response suggests that IL-1 alpha and TNF-alpha contribute to the radiation-induced component of pulmonary fibrosis, whereasIL-1 beta may have a protective function.
Abstract: Fibrosis, characterized by the accumulation of collagen, is a consequence of a chronic inflammatory response. The purpose of this study was to determine if tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and IL-1 beta mRNA expression are altered acutely after irradiation, during the so-called "latent" phase of pulmonary injury, and to examine if these alterations persist through the development of pneumonitis and fibrosis. Further, we wished to determine if these changes differ between two strains of mice which vary in their sensitivity to radiation. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 5 or 12.5 Gy to the thorax. Total lung RNA was prepared and immobilized by slot blotting and hybridized with radiolabeled cDNA probes encoding for TNF-alpha, IL-1 alpha and IL-1 beta. Autoradiographic data were quantified by video densitometry and results normalized to a control probe encoding for glyceraldehyde-3-phosphate dehydrogenase. It was found that TNF-alpha mRNA levels were increased in C57BL/6 mice at days 1 and 7 postirradiation after 5 Gy and day 14 postirradiation after both 5 and 12.5 Gy, and IL-1 alpha mRNA levels were increased in C57BL/6 mice at days 56, 112 and 182 postirradiation after both 5 and 12.5 Gy, and IL-1 beta mRNA levels in the C3H/HeJ mice were increased at days 56 and 182 postirradiation after 12.5 Gy. In summary, these studies demonstrated early and persistent alterations in TNF-alpha, IL-1 alpha and IL-1 beta mRNA levels even at the lower dose (5 Gy). The temporal relationship between the elevation of these cytokines and the strain-dependent variation in fibrosis response suggests that IL-1 alpha and TNF-alpha contribute to the radiation-induced component of pulmonary fibrosis, whereas IL-1 beta may have a protective function.
188 citations
TL;DR: Rydberg et al. as discussed by the authors developed a general theoretical model for the interaction of ionizing radiation with chromatin, which is modeled as a 30nm-diameter solenoidal fiber comprised of 20 turns of nucleosomes.
Abstract: We have developed a general theoretical model for the interaction of ionizing radiation with chromatin. Chromatin is modeled as a 30-nm-diameter solenoidal fiber comprised of 20 turns of nucleosomes, 6 nucleosomes per turn. Charged-particle tracks are modeled by partitioning the energy deposition between primary track core, resulting from glancing collisions with 100 eV or less per event, and delta rays due to knock-on collisions involving energy transfers >100 eV. A Monte Carlo simulation incorporates damages due to the following molecular mechanisms: (1) ionization of water molecules leading to the formation of OH, H, eaq, etc.; (2) OH attack on sugar molecules leading to strand breaks: (3) OH attack on bases; (4) direct ionization of the sugar molecules leading to strand breaks; (5) direct ionization of the bases. Our calculations predict significant clustering of damage both locally, over regions up to 40 bp and over regions extending to several kilobase pairs. A characteristic feature of the regional damage predicted by our model is the production of short fragments of DNA associated with multiple nearby strand breaks. The shapes of the spectra of DNA fragment lengths depend on the symmetries or approximate symmetries of the chromatin structure. Such fragments have subsequently been detected experimentally and are reported in an accompanying paper (B. Rydberg, Radiat, Res. 145, 200-209, 1996) after exposure to both high- and low-LET radiation. The overall measured yields agree well quantitatively with the theoretical predictions. Our theoretical results predict the existence of a strong peak at about 85 bp, which represents the revolution period about the nucleosome. Other peaks at multiples of about 1,000 bp correspond to the periodicity of the particular solenoid model of chromatin used in these calculations. Theoretical results in combination with experimental data on fragmentation spectra may help determine the consensus or average structure of the chromatin fibers in mammalian DNA.
184 citations
TL;DR: The author examines the role of radioactivity in the formation of particles, and the role that radioactivity has played in the development of electronics since the invention of the atom.
Abstract: Preface to the First Edition. Preface to the Second Edition. Preface to the Third Edition. 1 About Atomic Physics and Radiation. 1.1 Classical Physics. 1.2 Discovery of X Rays. 1.3 Some Important Dates in Atomic and Radiation Physics. 1.4 Important Dates in Radiation Protection. 1.5 Sources and Levels of Radiation Exposure. 1.6 Suggested Reading. 2 Atomic Structure and Atomic Radiation. 2.1 The Atomic Nature of Matter (ca. 1900). 2.2 The Rutherford Nuclear Atom. 2.3 Bohr's Theory of the Hydrogen Atom. 2.4 Semiclassical Mechanics, 1913-1925. 2.5 Quantum Mechanics. 2.6 The Pauli Exclusion Principle. 2.7 Atomic Theory of the Periodic System. 2.8 Molecules. 2.9 Solids and Energy Bands. 2.10 Continuous and Characteristic X Rays. 2.11 Auger Electrons. 2.12 Suggested Reading. 2.13 Problems. 2.14 Answers. 3 The Nucleus and Nuclear Radiation 55 3.1 Nuclear Structure 55 3.2 Nuclear Binding Energies. 3.3 Alpha Decay. 3.4 Beta Decay (&beta -). 3.5 Gamma-Ray Emission. 3.6 Internal Conversion. 3.7 Orbital Electron Capture. 3.8 Positron Decay (&beta +). 3.9 Suggested Reading. 3.10 Problems. 3.11 Answers. 4 Radioactive Decay. 4.1 Activity. 4.2 Exponential Decay. 4.3 Specific Activity. 4.4 Serial Radioactive Decay. 4.5 Natural Radioactivity. 4.6 Radon and Radon Daughters. 4.7 Suggested Reading. 4.8 Problems. 4.9 Answers. 5 Interaction of Heavy Charged Particles with Matter. 5.1 Energy-Loss Mechanisms. 5.2 Maximum Energy Transfer in a Single Collision. 5.3 Single-Collision Energy-Loss Spectra. 5.4 Stopping Power. 5.5 Semiclassical Calculation of Stopping Power. 5.6 The Bethe Formula for Stopping Power. 5.7 Mean Excitation Energies. 5.8 Table for Computation of Stopping Powers. 5.9 Stopping Power of Water for Protons. 5.10 Range. 5.11 Slowing-Down Time. 5.12 Limitations of Bethe's Stopping-Power Formula. 5.13 Suggested Reading. 5.14 Problems. 5.15 Answers. 6 Interaction of Electrons with Matter. 6.1 Energy-Loss Mechanisms. 6.2 Collisional Stopping Power. 6.3 Radiative Stopping Power. 6.4 Radiation Yield. 6.5 Range. 6.6 Slowing-Down Time. 6.7 Examples of Electron Tracks in Water. 6.8 Suggested Reading. 6.9 Problems. 6.10 answers. 7 Phenomena Associated with Charged-Particle Tracks. 7.1 Delta Rays. 7.2 Restricted Stopping Power. 7.3 Linear Energy Transfer (LET). 7.4 Specific Ionization. 7.5 Energy Straggling. 7.6 Range Straggling. 7.7 Multiple Coulomb Scattering. 7.8 Suggested Reading. 7.9 Problems. 7.10 Answers. 8 Interaction of Photons with Matter. 8.1 Interaction Mechanisms. 8.2 Photoelectric Effect. 8.3 Energy-Momentum Requirements for Photon Absorption by an Electron. 8.4 Compton Effect. 8.5 Pair Production. 8.6 Photonuclear Reactions. 8.7 Attenuation Coef.cients. 8.8 Energy-Transfer and Energy-Absorption Coef.cients. 8.9 Calculation of Energy Absorption and Energy Transfer. 8.10 Suggested Reading. 8.11 Problems. 8.12 Answers. 9 Neutrons, Fission, and Criticality. 9.1 Introduction. 9.2 Neutron Sources. 9.3 Classification of Neutrons. 9.4 Interactions with Matter. 9.5 Elastic Scattering. 9.6 Neutron-Proton Scattering Energy-Loss Spectrum. 9.7 Reactions. 9.8 Energetics of Threshold Reactions. 9.9 Neutron Activation. 9.10 Fission. 9.11 Criticality. 9.12 Suggested Reading. 9.13 Problems. 9.14 Answers. 10 Methods of Radiation Detection. 10.1 Ionization in Gases. Ionization Current. 10.2 Ionization in Semiconductors. 10.3 Scintillation. 10.4 Photographic Film. 10.5 Thermoluminescence. 10.6 Other Methods. 10.7 Neutron Detection. 10.8 Suggested Reading. 10.9 Problems. 10.10 Answers. 11 Statistics. 11.1 The Statistical World of Atoms and Radiation. 11.2 Radioactive Disintegration-Exponential Decay. 11.3 Radioactive Disintegration-a Bernoulli Process. 11.4 The Binomial Distribution. 11.5 The Poisson Distribution. 11.6 The Normal Distribution. 11.7 Error and Error Propagation. 11.8 Counting Radioactive Samples. 11.9 Minimum Significant Measured Activity-Type-I Errors. 11.10 Minimum Detectable True Activity-Type-II Errors. 11.11 Criteria for Radiobioassay, HPS Nl3.30-1996. 11.12 Instrument Response. 11.13 Monte Carlo Simulation of Radiation Transport. 11.14 Suggested Reading. 11.15 Problems. 11.16 Answers. 12 Radiation Dosimetry. 12.1 Introduction. 12.2 Quantities and Units. 12.3 Measurement of Exposure. 12.4 Measurement of Absorbed Dose. 12.5 Measurement of X- and Gamma-Ray Dose. 12.6 Neutron Dosimetry. 12.7 Dose Measurements for Charged-Particle Beams. 12.8 Determination of LET. 12.9 Dose Calculations. 12.10 Other Dosimetric Concepts and Quantities. 12.11 Suggested Reading. 12.12 Problems. 12.13 Answers. 13 Chemical and Biological Effects of Radiation. 13.1 Time Frame for Radiation Effects. 13.2 Physical and Prechemical Chances in Irradiated Water. 13.3 Chemical Stage. 13.4 Examples of Calculated Charged-Particle Tracks in Water. 13.5 Chemical Yields in Water. 13.6 Biological Effects. 13.7 Sources of Human Data. 13.8 The Acute Radiation Syndrome. 13.9 Delayed Somatic Effects. 13.10 Irradiation of Mammalian Embryo and Fetus. 13.11 Genetic Effects. 13.12 Radiation Biology. 13.13 Dose-Response Relationships. 13.14 Factors Affecting Dose Response. 13.15 Suggested Reading. 13.16 Problems. 13.17 Answers. 14 Radiation-Protection Criteria and Exposure Limits. 14.1 Objective of Radiation Protection. 14.2 Elements of Radiation-Protection Programs. 14.3 The NCRP and ICRP. 14.4 NCRP/ICRP Dosimetric Quantities. 14.5 Risk Estimates for Radiation Protection. 14.6 Current Exposure Limits of the NCRP and ICRP. 14.7 Occupational Limits in the Dose-Equivalent System. 14.8 The \"2007 ICRP Recommendations\". 14.9 ICRU Operational Quantities. 14.10 Probability of Causation. 14.11 Suggested Reading. 14.12 Problems. 14.13 Answers. 15 External Radiation Protection. 15.1 Distance, Time, and Shielding. 15.2 Gamma-Ray Shielding. 15.3 Shielding in X-Ray Installations. 15.4 Protection from Beta Radiation. 15.5 Neutron Shielding. 15.6 Suggested Reading. 15.7 Problems. 15.8 Answers. 16 Internal Dosimetry and Radiation Protection. 16.1 Objectives. 16.2 ICRP Publication 89. 16.3 Methodology. 16.4 ICRP-30 Dosimetric Model for the Respiratory System. 16.5 ICRP-66 Human Respiratory Tract Model. 16.6 ICRP-30 Dosimetric Model for the Gastrointestinal Tract. 16.7 Organ Activities as Functions of Time. 16.8 Specific Absorbed Fraction, Specific Effective Energy, and Committed Quantities. 16.9 Number of Transformations in Source Organs over 50 Y. 16.10 Dosimetric Model for Bone. 16.11 ICRP-30 Dosimetric Model for Submersion in a Radioactive Gas Cloud. 16.12 Selected ICRP-30 Metabolic Data for Reference Man. 16.13 Suggested Reading. 16.14 Problems. 16.15 Answers. Appendices. A Physical Constants. B Units and Conversion Factors. C Some Basic Formulas of Physics (MKS and CCS Units). Classical Mechanics. Relativistic Mechanics (units same as in classical mechanics). Electromagnetic Theory. Quantum Mechanics. D Selected Data on Nuclides. E Statistical Derivations. Binomial Distribution. Mean. Standard Deviation. Poisson Distribution. Normalization. Mean. Standard Deviation. Normal Distribution. Error Propagation. Index.
TL;DR: Three reaction pathways leading to the reduction of metal ions were proposed: reduction by hydrogen atoms; reduction by reducing radicals formed via reactions of hydroxyl radicals or hydrogen atoms with the additives; and reduction by radicals formed from thermal reaction of the additives at the interfacial region between cavitation bubbles and bulk solution and/or in the cavities.
Abstract: Gold(III) ions in aqueous solutions of NaAuCl4 were reduced to form gold particles by ultrasonic irradiation. The rate of formation of gold particles was accelerated in the presence of certain organic additives such as surfactants, water-soluble polymers and aliphatic alcohols and ketones. The rates of formation of gold particles from 1 mM Au(III) ions in pure water were 3 microM min-1 under argon atmosphere and approximately zero under air, and in solutions containing additive the rates were 9-133 microM min-1 under argon and 8-40 microM min-1 under air. Surfactants stabilized the particles as colloidal state for more than several months. The rates of formation of both hydrogen atoms and hydroxyl radicals were estimated to be equal to 25 microM min-1 in the sonolysis of pure water under argon. Three reaction pathways leading to the reduction of metal ions were proposed: (1) reduction by hydrogen atoms; (2) reduction by reducing radicals formed via reactions of hydroxyl radicals or hydrogen atoms with the additives; (3) reduction by radicals formed from thermal reaction of the additives at the interfacial region between cavitation bubbles and bulk solution and/or in the cavities. The order of the contribution of these three pathways to the reduction of gold ions was (3) > (2) > (1) in most cases. The number averages of the size of gold particles formed in surfactant solutions under argon atmosphere were about 10 nm with a fairly narrow size distribution.
TL;DR: The data presented identify the epidermal growth factor receptor protein tyrosine kinase associated with the plasma membrane as one target for ionizing radiation in the dose range used in radiotherapy.
Abstract: In an effort to identify events initiating up-regulation of epidermal growth factor receptor after single and repeated radiation exposures, we investigated the role of epidermal growth factor receptor, a receptor protein tyrosine kinase, in radiation-induced signal transduction. Human malignant mammary, MCF-7, and squamous, A431, cells showed low baseline phospho-tyrosine levels of epidermal growth factor receptor, permitting reproducible dose-dependent stimulation of epidermal growth factor receptor autophosphorylation after exposure to epidermal growth factor. MCF-7 cells exhibited a mean 2.3-fold increase (95% confidence interval: 1.91, 2.65; P < 0.0001) in levels of epidermal growth factor phosphorylation in response to exposures of 2 Gy, which was substantially less than the epidermal growth factor receptor Y phosphorylation induced by epidermal growth factor. A quantitatively similar radiation response was seen in A431 cells. In the dose range of 1 to 4 Gy, no clear dose response was seen. There was a rapid induction of radiation-induced epidermal growth factor receptor Y phosphorylation, starting within 2 min, with maximum values between 0.5 and 5 min after radiation exposure followed by a slower decline to baseline levels after 20 min. The data presented identify the epidermal growth factor receptor protein tyrosine kinase associated with the plasma membrane as one target for ionizing radiation in the dose range used in radiotherapy.
TL;DR: The results illustrate that theUse of a single RBE value in different irradiation protocols can be an oversimplification, and argues for the use of "proton gray doses" rather than "gamma-ray equivalent grays."
Abstract: Measurements of relative biological effectiveness (RBE) have been made on the range-modulated 70 MeV proton beam at TRIUMF using a precise cell sorting survival assay. In this study, Chinese hamster V79-WNRE cells were suspended in medium containing liquid gelatin at 37 degrees C in irradiation tubes and the gel was allowed to solidify by cooling to 4 degrees C. Complete cell survival responses were measured at 11 positions with 2 mm spacing within a proton stopping peak width of approximately 2 cm. Survival responses after proton irradiation were compared with responses to 60Co gamma rays measured at the same time, and RBE values were determined as a function of both dose and depth. Above doses of 4 Gy, the average RBE for these cells throughout the modulated proton stopping distribution was 1.21 +/- 0.05, measured at a survival of 1%. However, we also observed that, within the spread-out Bragg peak, the RBE increased with increasing depth, from approximately 1.2 at the proximal part to > 1.3 at the distal part of the peak. At the distal edge of the stopping distribution, the RBE value increased significantly, to an extent that may be of concern when this region of the treatment volume is close to sensitive tissues. Below 4 Gy, the RBE value was also dependent on radiation dose, increasing significantly to values of approximately 1.37 and 1.56 at 2 and 1 Gy, respectively. Our results illustrate that the use of a single RBE value in different irradiation protocols can be an oversimplification, and argues for the use of "proton gray doses" rather than "gamma-ray equivalent grays."
TL;DR: The results suggest that a dose-dependent alteration in the processing of DNA damage over the initial low-dose region of cell survival may contribute to radioresistance in some cell lines.
Abstract: It is well known that cells of human tumor cell lines display a wide range of sensitivity to radiation, at least a part of which can be attributed to different capacities to process and repair radiation damage correctly. We have examined the response to very low-dose radiation of cells of five human tumor cell lines that display varying sensitivity to radiation, using an improved assay for measurement of radiation survival. This assay improves on the precision of conventional techniques by accurately determining the numbers of cells at risk, and has allowed us to measure radiation survival to doses as low as 0.05 Gy. Because of the statistical limitations in measuring radiation survival at very low doses, extensive averaging of data was used to determine the survival response accurately. Our results show that the four most resistant cell lines exhibit a region of initial low-dose hypersensitivity. This hypersensitivity is followed by an increase in radioresistance over the dose range 0.3 to 0.7 Gy, beyond...
TL;DR: There appears to be a good correlation between those thiols that cause loss of clonogenicity and those that induce apoptosis, suggesting similar mechanisms may be involved in both end points.
Abstract: Under certain conditions, many radioprotective thiols can be toxic, causing loss of colony-forming ability in cultured mammalian cells in a biphasic fashion whereby the thiols are not toxic at high or low concentrations of the drug, but cause decreased clonogenicity at intermediate (0.2-1.0 mM) drug levels. This symposium paper summarizes our studies using dithiothreitol (DTT) as a model thiol to demonstrate the role of Fenton chemistry in thiol toxicity. The toxicity of DTT in V79 cells has several characteristics: it is dependent on the medium used during exposure of cells to the drug; the toxicity is decreased or prevented by addition of catalase exogenously, but superoxide dismutase has no effect; the toxicity is increased by addition of copper, either free or derived from ceruloplasmin in serum; and the toxicity can be modified intracellularly by altering glucose availability or pentose cycle activity. Thus the data are consistent with a mechanism whereby DTT oxidation produces H2O2 in a reaction catalyzed by metals, predominantly copper, followed by reaction of H2O2 in a metal-catalyzed Fenton reaction to produce the ultimate toxic species, .OH. Studies comparing 12 thiols have shown that the magnitude of cell killing and pattern of dependence on thiol concentration vary among the different agents, with the toxicity depending on the interplay between the rates of two reactions: thiol oxidation and the reaction between the thiol and the H2O2 produced during the thiol oxidation. The addition of other metals, e.g. Zn2+, and metal chelators, e.g. EDTA, can also alter DTT toxicity by altering the rates of thiol oxidation or the Fenton reaction. Recent studies have shown that in certain cell lines thiols can also cause apoptosis in a biphasic pattern, with little apoptosis at low or high drug concentrations but greatly increased apoptosis levels at intermediate (approximately 3 mM) thiol concentrations. There appears to be a good correlation between those thiols that cause loss of clonogenicity and those that induce apoptosis, suggesting similar mechanisms may be involved in both end points. However, thiol-induced apoptosis is not prevented by addition of exogenous catalase. These observations are discussed in relation to the possible role of Fenton chemistry in induction of apoptosis by thiols.
TL;DR: The induction of base damage products in gamma-irradiated DNA, hydrated between 2.5 and 32.8 moles of water per mole of nucleotide (tau), was investigated using the gas chromatography/mass spectrometry-selected ion monitoring technique, finding the yields were found to be dependent on the extent of the hydration when the DNA was irradiated under nitrogen.
Abstract: The induction of base damage products in γ-irradiated DNA, hydrated between 2.5 and 32.8 moles of water per mole of nucleotide (Γ), was investigated using the gas chromatography/mass spectrometry-selected ion monitoring technique. In general, the yields of the measured base damage products were found to be dependent on the extent of the hydration when the DNA was irradiated under nitrogen. At low hydrations (Γ ≤ 13), the highest yields of the measured products were found for 7,8-dihydro-8-oxo-guanine, 5,6-dihydrothymine and, to a lesser extent, 2,6-diamino-4-oxo-5-formamidopyrimidine, products which are consistent with the base radicals found in low-temperature ESR studies. At higher hydrations (Γ ≤ 13), changes in DNA conformation and an increase in the attack of bulk water radicals on DNA play a significant role in the formation of radiation-induced DNA base damage products. Additional findings in our study include: (1) the sum of the yields of the products formed from electron-loss centers is greater t...
TL;DR: Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study.
Abstract: A wide-ranging search for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR1Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7) for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR1Sv = 9.3 (3.5-30.6)], and most or all of that for benign tumors corresponded to Warthin's tumor [12 cases, RR1Sv = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR1Sv = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin's tumor [RR1Sv = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study.
TL;DR: The results of this study suggest that apoptosis is an important mechanism of heat-induced cell killing in some cell lines, and the effects of the hsp-70 and c-myc genes on the thermosensitivity of cells are correlated with their modulation of apoptosis.
Abstract: We studied heat-induced apoptosis and loss of clonogenicity in Rat-1 fibroblasts, thermotolerant Rat-1 (TT Rat-1), Rat-1 transfected with the human hsp-70 gene (M21) and Rat-1 transfected with the ...
TL;DR: Data indicate that the rapid (24 h) inactivation of irradiated DU-145 cells results from apoptosis and accounts for about 5% of the single-hit killing measured by clonogenic assay.
Abstract: Radiation-induced apoptosis detected by gel electrophoresis was measured in cells of three human prostate carcinoma cell lines (TSU, PC-3 and DU-145) and compared to their intrinsic radiosensitivities as measured by clonogenic assays. The intrinsic radiosensitivities of each cell line were defined by their α and β coefficients and their surviving fraction at 2 Gy, derived from complete survival curves. The temporal expression and kinetics of radiation-induced apoptosis for DU-145 cells, the human prostate carcinoma cell line which expressed the highest rate of radiation-induced apoptosis, was characterized further by differential sedimentation and the immunofluorescence assay (Apoptag®) which was specific for 3′-OH ends in cellular DNA. Cell viability was measured microscopically with trypan blue staining. Cell survival after various doses was computer-fitted to either a simple linear or a linear-quadratic equation. Twenty-four hours after a 10-Gy dose of137 Cs γ rays, DNA fragmentation to nucleosome mult...
TL;DR: The free radicals produced from the irradiation of hydrated DNA with a heavy-ion beam have been investigated by ESR spectroscopy and a new phosphorus-centered radical species is identified.
Abstract: The free radicals produced from the irradiation of hydrated DNA with a heavy-ion beam have been investigated by ESR spectroscopy. The dominant free radical species formed after 60 MeV/nucleon (16)O(8+) ion-beam irradiations at low temperatures (77 K) are the same as those previously identified from studies using low-LET radiation, pyrimidine electron-gain radicals and purine electron-loss radicals; however, greater relative amounts of neutral carbon-centered radicals are found with the higher-LET radiation, and a new phosphorus-centered radical is identified. The fraction of neutral carbon radicals is also found to increase along the ion-beam track with the highest amounts found in the Bragg peak. The neutral carbon-centered radicals likely arise in part from the sugar moiety. The G values found for total trapped radicals at 77 K are significantly smaller for the (16)O(8+) ion beam than those found for low-LET radiation. The new phosphorus-centered radical species is identified by its large 31P parallel hyperfine coupling of about 780 G as a phosphoryl radical. This species is produced linearly with dose and is not found in significant amounts in DNA irradiated with low-LET radiation. The phosphoryl radical must be produced by the fragmentation of a P-O bond and suggests the possibility of a direct strand break. The yield of phosphoryl species is small (about 0.1% of all radicals); however, it clearly indicates that new mechanisms of damage which are not significant for low-LET radiation must be considered for high-LET radiation.
TL;DR: A G2-phase assay is devised which appears to be giving promising results and is applied to cases of ataxia telangiectasia, xeroderma pigmentosum, familial adenomatous polyposis and the syndromes but has been unable to discriminate between these groups and controls except for AT homozygotes.
Abstract: Sanford et al. have reported that G{sub 2}-phase cells from many heritable cancer-prone conditions exhibit higher yields of X-ray-induced chromosome damage than those found in the majority of healthy controls. We have applied their protocol to lymphocytes of a group of control and cancer-prone individuals to see if we could confirm these observations. For control donors we observed higher aberration yields, different kinetics and more interexperiment variability than found by Sanford et al. These differences could not be attributed to unavoidable minor variations in procedures (e.g. serum batches, glassware washing methods), but the difference in X-ray qualities used in the two laboratories may have made a small contribution to the discrepancies. We attribute some of our experimental variability to the fact that, to varying extents in different experiments, centrifugation of cells prior to irradiation can slow down the progression of cells into metaphase and that cells can continue to repair during the harvesting procedure (centrifugation and hypotonic treatment). We have applied the assay to cases of ataxia telangiectasia (AT, homozygotes and heterozygotes), xeroderma pigmentosum (homozygotes and heterozygotes), familiar adenomatous polyposis and the syndromes Li-Fraumeni, basal cell nevus, Down`s and Fanconi`s but have been unable to discriminate between these groups andmore » controls except for AT homozygotes. By including a control sample in parallel with samples from cancer-prone groups we found a significant difference in mean aberration yields between controls and AT homozygotes and heterozygotes, but not for the other groups. Since technical features could explain the discrepancies between our laboratories, we have devised our own G{sub 2}-phase assay which appears to be giving promising results. 35 refs., 24 figs., 6 tabs.« less
TL;DR: Using five transplantable murine tumors, measurements of tumor hypoxia have been made with two techniques which have the potential to be used for assessing oxygenation in human tumors and have been compared with an established radiobiological technique, the paired survival assay.
Abstract: Using five transplantable murine tumors (SCC-VII, B16F1, KHT-C, KHT-LP1, RIF-1), measurements of tumor hypoxia have been made with two techniques which have the potential to be used for assessing oxygenation in human tumors (the Eppendorf $p{\rm O}_{2}$ Histograph and binding of $[{}^{3}{\rm H}]\text{misonidazole}$) and have been compared with an established radiobiological technique, the paired survival assay. There were significant differences in the $p{\rm O}_{2}$ measurements made in individual tumors both within and between the five different tumor types. Significant differences between the tumor types were also found for the $[{}^{3}{\rm H}]\text{misonidazole}$ binding. A correlation was observed between the mean values of the hypoxic proportion as measured by the paired survival assay and the mean binding of $[{}^{3}{\rm H}]\text{misonidazole}$ as measured by both tumor activity in dpm/100 mg tissue (r = 0.94, P = 0.02) and the tumor-to-muscle activity ratio (r = 0.87, P = 0.06). No biologically si...
TL;DR: It is suggested that protraction of dose may result in a lower risk than an acute X-ray exposure of the same total dose when exposure to 131I is combined with data from the A-bomb survivors.
Abstract: To provide quantitative data on the risk of thyroid cancer after exposure to131 I, 34,104 patients administered131 I for diagnostic purposes were followed for up to 40 years. The mean thyroid dose ...
TL;DR: The goal of the studies presented here was to determine if the radiosensitivity of fibroblasts in vitro isolated from mouse lungs was correlated with the severity of radiation- induced fibrosis in the lungs of two inbred strains of mice previously shown to differ markedly in their susceptibility to radiation-induced lung fibrosis.
Abstract: Radiation-induced pneumonitis and fibrosis in the lung after treatment to the thoracic cavity for malignant disease currently limit the maximum tolerated dose to that region. It has been suggested that heterogeneity in susceptibility to radiation-induced fibrosis exists in the population, implying that the lung tolerance dose is defined by a sensitive subset of the patient population. Studies of radiotherapy patients have indicated that the survival at 2 Gy (SF2) of cultured skin fibroblasts correlates with the incidence and severity of postirradiation damage in a number of tissues, suggesting that this assay may be a useful predictor of late tissue effects. The goal of the studies presented here was to determine if the radiosensitivity of fibroblasts in vitro isolated from mouse lungs was correlated with the severity of radiation-induced fibrosis in the lungs of two inbred strains of mice previously shown to differ markedly in their susceptibility to radiation-induced lung fibrosis: the C3Hf/Kam strain, classified as fibrosis-resistant, and the C57BL/6J strain, classified as fibrosis-prone. Quantitative measurements of lung fibrosis after irradiation were compared to SF2 values for fibroblasts of skin and lung cultured from each strain. Lung fibrosis was quantified, using computerized image analysis, as the percentage of fibrosis on Masson's Trichrome-stained lung sections from both strains after single doses of radiation to the thorax. For the measurements of SF2, fibroblasts plated at the second passage and grown to confluence were given single doses of radiation ranging from 0 to 6 Gy. Survival curves were constructed and SF2 values obtained from a linear-quadratic fit to the data. The radiosensitivity of fibroblasts from the lung and skin of SCID mice was determined and served as a positive control. The percentage of radiation-induced lung fibrosis was significantly different between the two strains, 5.1% and 0.2% in the C57 strain and C3H strain, respectively. Follow-up of long-term survivors (two mice) from the C3H strain did not change this conclusion. However, the lung fibroblast SF2 for the C57BL/6J strain (fibrosis-prone), 0.50 +/- 0.03, was not statistically different from the C3Hf/Kam strain (fibrosis-resistant), 0.55 +/- 0.07. These data indicate that in vitro radiosensitivity of lung fibroblasts as assayed by survival at 2 Gy does not correlate with the development of lung fibrosis in this mouse model. The SF2 for lung fibroblasts from SCID mice was 0.10. Similar SF2 values were obtained for both the C3Hf/Kam mouse lung and skin fibroblasts, 0.55 and 0.56, respectively, and C57BL/6J mouse lung and skin fibroblasts, 0.50 and 0.52, respectively, indicating that the radiosensitivity of fibroblasts isolated from lung and skin within a strain is the same.
TL;DR: It is demonstrated that lower fluence rates and/or fractionating the light dose delivered can improve the response of the RIF1 tumor to PDT but that the choice of dark intervals between fractions is critical.
Abstract: Various schedules of fractionated photodynamic therapy (PDT), delivered at two different light fluence rates, were investigated in the RIF1 tumor model in an attempt to minimize the development of hypoxia during PDT and thereby improve tumor response relative to single treatments. The photosensitizers Photofrin and meta-tetrahydroxyphenylchlorin (mTHPC) were used in combination with either interstitial or superficial illumination. For both methods of illumination, equal volumetric light doses gave similar tumor responses, as measured by tumor regrowth times and number of cures. Fractionation of superficial illumination did not generally improve tumor response compared with a single illumination with the same total light dose. The only fractionated schedules which demonstrated a trend for increased cure were six fractions of superficial illumination given with short (1 h) dark periods between illuminations. Using both photosensitizers, an increase in tumor regrowth time occurred when tumors were illuminate...
TL;DR: Spermine at physiological levels and ionic strength induces compaction and aggregation of SV40 DNA and minichromosomes resulting in marked radioprotection of the DNA against gamma-ray-induced formation of single-strand breaks, considered to be a major mechanism responsible for radioprotsection of cellular DNA.
Abstract: Spermine at physiological levels and ionic strength induces compaction and aggregation of SV40 DNA and minichromosomes resulting in marked radioprotection of the DNA against γ-ray-induced formation of single-strand breaks. This phenomenon, termed the PICA effect, results in yields of single-strand breaks in DNA and minichromosomes comparable to those found with intact cells and is considered to be a major mechanism responsible for radioprotection of cellular DNA.
TL;DR: It is demonstrated that the variations in sensitivity among these sensitive and resistant mice are a result of inherent differences in the sensitivity of the mammary epithelial cells to radiation-induced transformation.
Abstract: Variations in sensitivity to radiation-induced mammary cancer among different strains of mice are well known. However, the reasons for these variations have not been determined. In the present study, the cell dissociation assay was used to determine the radiation-induced transformation frequencies in sensitive BALB/c mice and resistant C57BL mice as well as the resistant hybrid B6Cf{sub 1} independent of host environment. The influence of host environment on the progression of transformed cells to the neoplastic phenotype was also examined. Results demonstrated that the variations in sensitivity among these sensitive and resistant mice are a result of inherent differences in the sensitivity of the mammary epithelial cells to radiation-induced transformation. Under the conditions used, host environment played no role in the initiation of transformed cells by radiation or in the progression of these cells to the neoplastic phenotype. 19 refs., 1 tab.
TL;DR: The yields of hydroxyl radicals, as G values and "destruction constants," in the DNA hydration shell as a function of the level of hydration are reported, suggesting that only a few holes which escape recombination in spurs charge-transfer to the DNA are found.
Abstract: In this work, we report the yields of hydroxyl radicals, as G values and "destruction constants," in the DNA hydration shell as a function of the level of hydration. Electron spin resonance spectroscopy of gamma-irradiated DNA at low temperatures is employed for detection of the hydroxyl radical. Due to the glassy nature of the DNA hydration layer at low temperature, the hydroxyl radical gives a broad ESR resonance which is easily distinguished from the hydroxyl radical in a polycrystalline ice phase; thus .OH in both glassy and ice regions is quantified. Three regimes of radiological behavior for waters of hydration in DNA are found. For the first approximately 9 waters/nucleotide (which are glassy), no significant amounts of .OH are found, suggesting hole transfer to DNA. The second regime of hydration waters comprises up to about 12 additional glassy waters/nucleotide (gamma = 21). In this regime, substantial amounts of glassy .OH are found, suggesting that only a few holes which escape recombination in spurs charge-transfer to the DNA. In these two glassy regimes no trapped electrons are found, which is in accord with previous work that has reported that all electrons which do not undergo recombination in spurs transfer to DNA. The third regime of hydration water is comprised of bulk (or bulk-like) polycrystalline ice which forms when levels of hydration over 21 waters/nucleotide are reached. These waters form a separate phase from the DNA/glassy-water system, and neither hole nor substantial electron transfer to the DNA occurs; .OH in this ice phase is observed with G values that vary slightly with the amount of water in the ice phase, but which are close to the values found for pure ice.
TL;DR: Evidence is presented that a two-stage stochastic model of carcinogenesis used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol describes the data adequately and generates hypotheses regarding the mechanism of Radon-induced carcinogenesis.
Abstract: A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.