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PubMed2005

Differential oxidation of deoxyribose in DNA by gamma and alpha-particle radiation.

Emerging evidence points to the importance of deoxyribose oxidation in the toxicity of oxidative DNA damage, including the formation of protein-DNA crosslinks and base adducts. With the goal of understanding the differences in deoxyribose oxidation chemistry known to occur with different oxidants, we have compared the formation of one product of 3'-oxidation of deoxyribose in DNA, 3'-phosphoglycolaldehyde (PGA) residues, in isolated DNA and cells exposed to ionizing radiations. A recently developed gas chromatography/negative chemical ionization mass spectrometry method was used to quantify PGA residues in purified DNA and in human TK6 lymphoblastoid cells exposed to gamma radiation (60Co) and alpha particles (241Am). The level of PGA residues was then correlated with the total quantity of deoxyribose oxidation determined by plasmid topoisomer analysis. Alpha-particle irradiation (0-100 Gy) of purified DNA in 50 mM potassium phosphate (pH 7.4) produced a linear dose response of 0.13 PGA residues per 10(6) nucleotides per gray. When normalized to an estimate of the total number of deoxyribose oxidation events (2.0 per 10(6) nucleotides per gray), PGA formation occurred in 7% (+/-0.5) of deoxyribose oxidation events produced by alpha-particle radiation. In contrast, the efficiency of PGA formation in gamma-irradiated DNA was found to be 1% (+/-0.02), which indicates a shift in the chemistry of deoxyribose oxidation, possibly as a result of the different track structures of the two types of ionizing radiation. Studies with gamma radiation were extended to TK6 cells, in which it was observed that gamma radiation produced a linear dose response of 0.0019 PGA residues per 10(6) nucleotides per gray. This is consistent with an approximately 1000-fold quenching effect in cells, similar to the results of other published studies of oxidative DNA damage in vivo.

Alpha Particles↗

PubMed1990

Cytogenetic effects of extremely low doses of plutonium-238 alpha-particle irradiation in CHO K-1 cells.

CHO K-1 cells were irradiated during the G1 phase with 0.5-6 rad of alpha particles. There was no appreciable cell killing in this low dose range. Significantly increased frequencies of sister-chromatid exchanges were induced by doses as low as 0.5 rad of alpha-particle irradiation, whereas increased numbers of chromosomal aberrations were observed following exposure to 2 rad. These results suggest that very low doses of alpha radiation may lead to radiation-induced genetic alterations.

Alpha Particles↗

PubMed2006

Current status of alpha-particle spectrometry.

This paper describes the status of alpha-particle spectrometry. Some of the main contributions made to this field in the last years are reviewed. Topics covered include instrumentation, source characterization, numerical analysis, Monte Carlo simulations and applications.

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PubMed1990

Radiobiology of alpha particles. I. Exposure system and dosimetry.

A 238Pu alpha-particle exposure apparatus was designed and constructed for use in radiobiological studies with cultured cell systems. The system provides a wide dynamic range of absorbed doses and a uniform radiation field. Average dose rate in air was measured with a small-volume ionization chamber. Estimates of dose rate at the cell surface were obtained from measurements taken with a silicon surface barrier detector. Particle fluence uniformity and fluence rate were measured using track etch procedures. The design and dosimetric characterization of the apparatus are discussed.

Alpha Particles↗

PubMed2003

Image processing tools for alpha-particle track-etch dosimetry.

In cases where both the source and cell geometry are well known, track-etch dosimetry allows the potential for individual cell dosimetry. However, analysis of track-etch images is both tedious and time-consuming. We describe here several image processing tools that we are using in conjunction with a track-etch based irradiator. Briefly, cells grown on LR 115 (a track-etch material) are irradiated from below by a collimated, planar alpha-particle source. Prior to irradiation, images of the cells are obtained. A computer program reads each image and automatically determines the location of individual cells. Next, the algorithm automatically identifies the cellular and nuclear boundaries. Following irradiation, and after the cells have reached their biological endpoint (e.g., cell survival), the cell dish is etched and images are obtained of alpha-particle tracks. Using the characteristic background pattern in the LR 115, the etched images are spatially registered to the original images. These two sets of images are then superimposed to create a composite image of the cells and associated alpha-particle tracks. Incorporating this tool into our irradiation scheme will enable more efficient analysis of the large amounts of data that are essential in assessing biological endpoints.

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PubMed1997

DNA complex lesions induced by protons and alpha-particles: track structure characteristics determining linear energy transfer and particle type dependence.

The yield of DNA double-strand breaks (dsb) and DNA complex lesions induced by protons and alpha-particles of various energies was simulated using a Monte Carlo track structure code (MOCA15) and a simple model of the DNA molecule. DNA breaks of different complexity were analysed. The linear energy transfer (LET) and particle-type dependence of lesions of higher complexity seems to confirm the importance of clustered damage in DNA as a relevant step leading to biological endpoints such as cell inactivation. The detailed structure of proton and alpha-particle tracks was analysed to identify the main characteristics possibly responsible for such a dependence. The role of the primary ion and of its secondary electrons in inducing dsb and complex lesions is described, showing that the relative contribution of secondary electron tracks alone in inducing clustered lesions is almost negligible at high LET, but tends to dominate below = 10 keV/micron. This is consistent with the observed similar effectiveness of low-LET fast particle radiation and sparsely ionizing radiation such as x-rays. The dependence on LET and particle type is mainly due to energy deposition events of the primary ion together with short range electrons surrounding the ion track; the yield of complex lesions due to secondary electron tracks alone is substantially LET independent. The radial distributions of the energy contributing to the induction of complex lesions were analyzed and compared with the radial distributions of energy deposition of the full tracks. The results suggest that the stochastic behaviour (i.e. cluster properties) of the energy deposition pattern within a radius of a few nanometers around the ion track plays a relevant role in determining the biological radiation effectiveness.

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PubMed2000

No dose-dependence of DNA double-strand break misrejoining following alpha-particle irradiation.

PURPOSE: To investigate whether an explanation for the high effectiveness of densely ionizing radiation with regard to complex biological endpoints can be derived from measurements of radiation-induced double-strand break (DSB) misrejoining. MATERIALS AND METHODS: Misrejoining of radiation-induced DSB in normal human fibroblasts was determined by comparing hybridization analysis of large restriction fragments as a measure for correct rejoining, with results from a conventional pulsed-field gel electrophoresis technique (FAR) that measures total DSB rejoining. In order to investigate DSB misrejoining at doses for which chromosome aberration data are available, a dose fractionation protocol was applied so that the number of DSB at any given timepoint was low but the cumulative amount of misrejoined DSB sufficient for detection and precise quantitation. RESULTS AND CONCLUSION: After an acute 80Gy alpha-particle exposure and a repair incubation period of 24 h, 50% of all initially induced DSB were misrejoined, in agreement with data obtained for X-rays. X-irrradiation with 16 x 5 Gy, 8 x 10 Gy, 4 x 20 Gy, or 2 x 40 Gy and repair incubation of 24 h following each individual dose fraction was recently reported to yield misrejoining frequencies that strongly decrease with increasing fractionation (Löbrich et al. 2000; Genes, Chromosomes and Cancer, 27, 59-68). In the present study, constant misrejoining frequencies of 50% were observed after alpha-particle exposure with the same fractionation protocol. This difference between alpha-particles and X-rays is in accordance with the high biological effectiveness of densely ionizing radiation and provides a direct link between misrejoining of DSB and cytologically visible exchange aberrations. Further evidence suggests that if the same dose range is compared, the number of misrejoined DSB exceeds the number of microscopically visible aberrations by an order of magnitude for both radiation types, probably reflecting the high resolution of the hybridization approach compared with cytological techniques.

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PubMed2002

Energy deposition, cellular radiation effects and lung cancer risk by radon progeny alpha particles.

Slowing down spectra, LET spectra, hit probabilities, and radiation doses were simulated for the interaction of single 218Po and 214Po alpha particles with sensitive basal and secretory cell nuclei in the bronchial epithelium of human and rat lungs for defined exposure conditions. Probabilities per unit track length for transformation, derived from in vitro experiments with C3H 10T1/2 cells, were used to estimate transformation probabilities for randon progeny alpha particles in basal and secretory cells. Different weighting schemes were assumed to relate cellular hit probabilities, doses and transformation probabilities, obtained for different cell depths and airway generations, to lung cancer risk per unit exposure. In vitro transformation and in vivo lung cancer incidence were simulated by a state-vector model which provides a stochastic formulation of dose-rate dependent cellular transitions related to formation of double strand breaks, repair, inactivation, stimulated mitosis and promotion through loss of intercellular communication.

Alpha Particles↗

PubMed2002

Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures.

The role of oxidative metabolism in the up-regulation/activation of stress-induciblesignaling pathways as well as induction of micronucleus formation in bystander cells was investigated. By immunoblotting and in situ immunofluorescence, active Cu-Zn superoxide dismutase (SOD) enzyme and active catalase enzyme were shown to inhibit the up-regulation of p21(Waf1) as well as the induction of micronucleus formation in bystander cells from confluent cultures of normal human diploid fibroblasts irradiated with 0.3-3 cGy of alpha-particles. Enzyme activity assays indicated that exogenous SOD became significantly associated with the cells. Reactive oxygen species apparently derived from a flavin-containing oxidase enzyme [presumably an NAD(P)H-oxidase] appeared to be major contributors to the bystander-induced up-regulation of p53 and p21(Waf1) as well as micronucleus formation, as evidenced by the inhibition of these effects with diphenyliodonium. Rapid activation of nuclear factor kappaB, Raf-1, extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase and their downstream effectors activator protein 1, ELK-1, p90RSK, and activating transcription factor 2 was also observed in cultures exposed to very low fluences of alpha-particles. Significant attenuation in the activation of these kinases and transcription factors occurred in irradiated cultures treated with either SOD or catalase. Overall, these results support the hypothesis that superoxide and hydrogen peroxide produced by flavin-containing oxidase enzymes mediate the activation of several stress-inducible signaling pathways as well as micronucleus formation in bystander cells from cultures of human cells exposed to low fluences of alpha-particles.

Alpha Particles↗

PubMed2005

Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 2: radiolytic effects of 211At alpha-particles influence N-succinimidyl 3-211AT-astatobenzoate synthesis.

UNLABELLED: A variety of promising targeted radiotherapeutics labeled with alpha-emitters have been developed. Clinical investigation of these radiopharmaceuticals requires the production of high activity levels, which can be hindered by alpha-particle-mediated radiolytic effects on labeling chemistry. The purpose of this study was to investigate the effects of radiation dose on the synthesis of N-succinimidyl 3-(211)At-astatobenzoate (SAB), a compound used in our clinical trials for labeling antibodies with alpha-particle-emitting (211)At. METHODS: Yields for the synthesis of SAB as a function of the radiation dose received by the reaction medium were determined. The variables studied included the radiohalogenation precursors N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-(trimethylstannyl)benzoate (MeSTB); the solvents chloroform, benzene, and methanol; and the addition of acetic acid and the oxidant N-chlorosuccinimide. The (211)At product spectra were determined from high-performance liquid chromatograms and then plotted against radiation dose. RESULTS: SAB production declined rapidly with increasing dose, consistent with the documented radiolytic decomposition of BuSTB and MeSTB in chloroform. Even though these tin precursors were not appreciably degraded in benzene, SAB could not be produced in this solvent; instead, highly lipophilic (211)At-labeled species were generated in nearly quantitative yields. Although a dose-dependent decline in SAB yield also was observed in methanol, both in the presence and in the absence of an oxidant, the results were better than those obtained with the other solvents. An unexpected observation was that SAB could be obtained at a yield of greater than 30% when the reaction was run in methanol without the addition of acetic acid or an oxidant; these 2 components previously were considered essential for astatodestannylation. CONCLUSION: Radiolytic factors can play an important role in the synthesis of clinical-level activities of (211)At-labeled radiopharmaceuticals, necessitating the development of reaction conditions different from those that are used successfully at lower activity levels.

Alpha Particles↗

PubMed1979

Relative determination of W-values for alpha particles in tissue-equivalent and other gases.

W (the average energy to form an ion pair) for 5.4 MeV 241Am alpha particles in a Rossi-type tissue-equivalent (TE) gas, argon and methane was determined to an accuracy better than 0.2% using a new automated data handling system. A vibrating reed electrometer and current digitiser were used to measure the current produced by completely stopping the alpha particles in a large cylindrical ionisation chamber. A multichannel analyser, operating in a slow multiscaler mode, was used to store pulses from the current digitiser. The dwell time, of the order of 60 min per channel, was selected with an external timer gate. Current measurements were made at reduced pressures (200 Torr) to reduce ion recombination. The average current, over many repeated measurements, was compared to the current produced in nitrogen and its previously published W-value of 36.39+/-0.04 eV per ion pair. The resulting W-values were, in eV per ion pair, 26.29+/-0.05 for argon, 29.08+/-0.03 for methane and 30.72+/-0.04 for TE gas, which had an analysed composition of 64.6% methane, 32.4% CO2 and 2.7% nitrogen. Although the methane and argon values agree within 0.1% with previously published values, the value for TE is 1.2% lower than the single previously reported value.

Alpha Particles↗

PubMed2005

Immunoreactivity assay for alpha-particle emitting monoclonal antibody constructs.

Clinical trials using alpha-particle radiolabeled antibodies require a rapid and reproducible assay of the immunoreactivity of drugs. While live cell assays are typically used to determine the immunoreactive drug fraction, a fixed cell assay may replace the traditional live cell assay and offer the advantages of rapidity, easy availability and consistency for qualifying drugs for preclinical or clinical studies. We have identified optimal cell fixation and immunoreactivity assay conditions and have validated them by performing the fixed-cell assay in clinical trials.

Alpha Particles↗

PubMed2001

Recoil proton, alpha particle, and heavy ion impacts on microdosimetry and RBE of fast neutrons: analysis of kerma spectra calculated by Monte Carlo simulation.

Fast neutrons (FN) have a higher radio-biological effectiveness (RBE) compared with photons, however the mechanism of this increase remains a controversial issue. RBE variations are seen among various FN facilities and at the same facility when different tissue depths or thicknesses of hardening filters are used. These variations lead to uncertainties in dose reporting as well as in the comparisons of clinical results. Besides radiobiology and microdosimetry, another powerful method for the characterization of FN beams is the calculation of total proton and heavy ion kerma spectra. FLUKA and MCNP Monte Carlo code were used to simulate these kerma spectra following a set of microdosimetry measurements performed at the National Accelerator Centre. The calculated spectra confirmed major classical statements: RBE increase is linked to both slow energy protons and alpha particles yielded by (n,alpha) reactions on carbon and oxygen nuclei. The slow energy protons are produced by neutrons having an energy between 10 keV and 10 MeV, while the alpha particles are produced by neutrons having an energy between 10 keV and 15 MeV. Looking at the heavy ion kerma from <15 MeV and the proton kerma from neutrons <10 MeV, it is possible to anticipate y* and RBE trends.

Alpha Particles↗

PubMed1992

Induction of mutations by bismuth-212 alpha particles at two genetic loci in human B-lymphoblasts.

The human lymphoblast cell line TK6 was exposed to the alpha-particle-emitting radon daughter 212Bi by adding DTPA-chelated 212Bi directly to the cell suspension. Cytotoxicity and mutagenicity at two genetic loci were measured, and the molecular nature of mutant clones was studied by Southern blot analysis. Induced mutant fractions were 2.5 x 10(-5)/Gy at the hprt locus and 3.75 x 10(-5)/Gy at the tk locus. Molecular analysis of HPRT- mutant DNAs showed a high frequency (69%) of clones with partial or full deletions of the hprt gene among radiation-induced mutants compared with spontaneous mutants (31%). Chi-squared analyses of mutational spectra show a significant difference (P < or = 0.005) between spontaneous mutants and alpha-particle-induced mutants. Comparison with published studies of accelerator-produced heavy-ion exposures of TK6 cells indicates that the induction of mutations at the hprt locus, and perhaps a subset of mutations at the tk locus, is a simple linear function of particle fluence regardless of the ion species or its LET.

Alpha Particles↗

PubMedDate not supplied

Cell growth kinetics of the human cell line Colo-205 irradiated with photons and astatine-211 alpha-particles.

Cell growth kinetics following Astatine-211 (211At, alpha-particle emitter) and photon irradiation were studied for the human colorectal cell line Colo-205. A growth assay using 96-well plates was chosen. The growth kinetics could be simulated by assuming certain fractions of cells with various proliferative capacities, i.e. from none up to 5 cell doublings, in addition to the defined survivors with remaining unlimited clonogenic capacity. No significant difference in cell growth characteristics was seen between 211At and photon irradiation. The cell doubling time, as calculated from the increment in optical density, was compared with the results from BrdU experiments in the early phases of growth (Tpot = 18.5 +/- 0.6 h for LDR (low dose rate) photon irradiated and 20.3 +/- 0.8 hours for sham-irradiated cells 40-45 hours post-irradiation) confirming the transient accelerated growth of irradiated cells. No statistically significant difference in growth was found between LDR, MDR (medium dose rate) and HDR (high dose rate) photon irradiation.

Alpha Particles↗

PubMed2005

In situ visualization of DSBs to assess the extranuclear/extracellular effects induced by low-dose alpha-particle irradiation.

Extranuclear/extracellular effects may have a significant effect on low-dose radiation risk assessment as well as on the shape of the dose-response relationship. Numerous studies using different end points such as sister chromatid exchanges, micronuclei and mutation have shown that this phenomenon exists in many cell types. However, these end points mostly reflect the late events after radiation damage, and little is known about the early response in this phenomenon. DNA double-strand breaks (DSBs) induced by ionizing radiation or carcinogenic chemicals can be visualized in situ using gamma-H2AX immunofluorescence staining, and there is evidence that the number of gamma-H2AX foci can be closely correlated with DSBs induced. Here we used gamma-H2AX as a biomarker to assess the extranuclear/extracellular effects induced by low-dose alpha particles in situ. The results show that a greater fraction of positive cells with DSBs (48.6%) was observed than the number of cells whose nuclei were actually traversed by the 1-cGy dose of alpha particles (9.2%). The fraction of DSB-positive cells was greatly reduced after treatment with either lindane or DMSO. These results suggest that in situ visualization of DSBs can be used to assess radiation-induced extranuclear/extracellular effects soon after irradiation. Moreover, the in situ DSB assay may provide a means to evaluate the spatial effect on unirradiated cells that are located in the neighboring region of cells irradiated by alpha particles.

Alpha Particles↗

PubMed1984

Repair of DNA double-strand breaks as a determinant of RBE of alpha particles.

The role of repair of DNA double-strand breaks (dsb) in the determination of the RBE-value of alpha particles was studied using the temperature conditional radiosensitive diploid yeast mutant rad 54-3. This mutant is proficient in the repair of dsb at the permissive temperature of 23 degrees C at which it yields a shouldered survival curve, but it is dsb repair-deficient at the restrictive temperature of 36 degrees C at which it yields an exponential survival curve. At the permissive temperature the rad 54-3 mutant also shows liquid holding recovery of colony forming ability as a function of the liquid holding period. Thus, with this mutant it is possible to obtain survival curves involving no repair of dsb (immediate plating, 36 degrees C), partial repair of dsb (immediate plating, 23 degrees C) and gradually increasing levels of dsb repair by delayed plating after liquid holding periods of 24, 48 and 72 h. The RBE-values of densely ionizing 3.5 MeV alpha particles for cell killing relative to sparsely ionizing 30 MeV electrons have been determined as a function of the level of dsb repair. It is shown that the RBE-value is low and independent of dose when no repair of dsb is involved, whereas it becomes gradually larger with a gradual increase in the level of dsb repair.

Alpha Particles↗

PubMed1993

Alpha-particle dose to the liver and spleen tissues of Japanese Thorotrast patients.

We set out to establish an appropriate and convenient method for calculating alpha-particle absorbed doses to the liver and spleen of Thorotrast patients and to estimate a representative dose rate to the liver for the whole population of surviving and deceased Thorotrast patients in Japan. First, we determined steady-state activity ratios of 232Th progeny from 13 autopsy cases and found them to be identical to those reported in German subjects. Second, we estimated the alpha dose rates in 206 subjects at autopsy from radioactivity measurements and terminal weights of the organs. Combining these results with measurements of exhaled 220Rn in survivors, we considered the representative dose rates at injection to be 0.22 Gy y-1. Additionally, our data suggest that deposition in the spleen has previously been overestimated. This is an error with some bearing on the evaluation of leukemia risks from alpha-particle irradiation.

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