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PubMed1993

DNA double-strand break induction in yeast by X-rays and alpha-particles measured by pulsed-field gel electrophoresis.

Pulsed-field gel electrophoresis was used to separate the chromosomes of the diploid yeast Saccharomyces cerevisiae 211*B after irradiation with X-rays and alpha-particles. After electrophoresis, gels were stained with ethidium bromide, placed on a UV-transilluminator and photographed with a digitizing camera connected to a personal computer. The pictures obtained were processed with the help of specially developed software which allows for the correction of the camera's shading effect and background fluorescence. Linearity between DNA amount and fluorescence was demonstrated. Fluorescence intensity for the band with the lowest electrophoretic mobility was found to decrease exponentially with dose. Based on the known size of the native DNA molecules, double-strand break yields could be calculated. These were found to be (8.2 +/- 0.4) and (14.8 +/- 0.5)10(-12) (g/mol)-1 Gy-1 for 80 keV X-rays and 3.5 MeV 241Am alpha-particles respectively which gives a relative biological effectiveness of 1.8 +/- 0.1.

Alpha Particles↗

PubMed2005

Role of homologous recombination in the alpha-particle-induced bystander effect for sister chromatid exchanges and chromosomal aberrations.

The bystander effect for sister chromatid exchanges (SCEs) and chromosomal aberrations was examined in hamster cell lines deficient in either DNA-PKcs (V3 cells, deficient in nonhomologous end joining, NHEJ) or RAD51C (irs3 cells, deficient in homologous recombination, HR). Cells synchronized in G0/G1 phase were irradiated with very low fluences of alpha particles such that < 1% of the nuclei were traversed by an alpha particle. Wild-type cells showed a prominent bystander response for SCE induction; an even greater effect was observed in V3 cells. On the other hand, no significant induction of SCE was observed in the irs3 RAD51C-deficient bystander cells irradiated at various stages in the cell cycle. Whereas a marked bystander effect for chromosomal aberrations occurred in V3 cells, the induction of chromosomal aberrations in irs3 bystander cells was minimal and similar to that of wild-type cells. Based on these findings, we hypothesize that HR is essential for the induction of SCE in bystander cells; however, HR is unable to repair the DNA damage induced in NHEJ-deficient bystander cells that leads to either SCE or chromosomal aberrations.

Alpha Particles↗

PubMed2000

On the application of a radiation weighting factor for alpha particles in protection of non-human biota.

Radiation protection standards for non-human biota have been expressed in terms of absorbed dose. In calculating dose to biota, some investigators have modified the absorbed dose due to alpha particles by a factor of 20, based on the radiation weighting factor used in protection of humans, to account for the greater effectiveness of these radiations in producing biological damage. However, this value is intended to apply to stochastic health effects, primarily cancers, whereas deterministic effects have been the primary concern in protection of biota. Based on an analysis by the International Commission on Radiological Protection, the deterministic radiation weighting factor for alpha particles appears to lie in the range of about 5-10. Given the potential importance of this weighting factor in determining allowable levels of alpha-emitting radionuclides in the environment, regulatory authorities must be impressed with the need to develop an appropriate value for use in protection of biota. There also is a need to express doses and dose limits for biota in terms of a quantity other than absorbed dose and to develop an appropriate name for the biologically significant dose to biota.

Alpha Particles↗

PubMed1997

Radiation-induced genomic instability: delayed mutagenic and cytogenetic effects of X rays and alpha particles.

The frequency of mutations at the Hprt locus was measured in clonal populations of Chinese hamster ovary cells derived from single cells surviving exposure to 0-12 Gy of X rays or 2 Gy of alpha particles. Approximately 8-9% of 446 clonal populations examined 23 population doublings after irradiation showed high frequencies of late-arising mutations as indicated by mutant fractions 10(2)-10(4)-fold above background. The frequency with which such clones occurred was similar for alpha-particle irradiation and X irradiation, with no apparent dose dependence for X irradiation over the range of 4-12 Gy. The molecular structure of Hprt mutations was determined by analysis by multiplex polymerase chain reaction of all nine exons. Of mutations induced directly after exposure to X rays, 75% involved partial or total gene deletions. Only 19-23% of late-arising (delayed) mutations were associated with deletions, the preponderance of these being partial deletions involving one or two exons. This spectrum was very similar to that for spontaneously arising mutations. To determine whether delayed mutations were non-clonal, the spectrum of exons deleted was examined among 29 mutants with partial deletions derived from a single clonal population. The results indicated that at least 15 of these mutants arose independently. To examine the relationship between the occurrence of delayed mutations and chromosomal instability, 60 Hprt mutant subclones isolated from a clonal population showing a high frequency of delayed mutations were serially cultivated in vitro. Of these, 14 showed a slow-growth phenotype with a high frequency of polyploid cells (10-38%) and a markedly enhanced frequency of non-clonal chromosomal rearrangements including both chromosome-type and chromatid-type aberrations. These clones also showed a 3- to 30-fold increase in the frequency of ouabain-resistant mutations; no ouabain-resistant mutants were induced directly by X irradiation. These results suggest that among clones showing a high frequency of delayed mutations there may be a subpopulation of cells that are particularly unstable; selection for the slow-growth phenotype has the effect of selecting for this chromosomally unstable subpopulation.

Alpha Particles↗

PubMed1985

W value measurements for 241Am alpha particles in various gases.

Measurements of W, the mean energy expended per ion pair formed, have been performed for 241Am alpha particles stopping in a number of the gases commonly used in ionisation chambers. Both absolute and relative measurements were made with nitrogen used as the reference gas for the relative measurements. The absolute method entailed a simultaneous measurement of a quantity of charge and the number of alpha particles which produced that charge, whilst the relative approach simply required a determination of the ratio of ion currents. Results were obtained for methane-based tissue-equivalent gas, for its constituents, i.e. methane, carbon dioxide and nitrogen, for argon, and also for a gas mixture with a composition approximately equivalent to A-150 plastic.

Americium↗

PubMed2000

Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy.

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Alpha Particles↗

PubMed1993

Inactivation of haemopoietic stem cells by slow alpha-particles.

Inactivation of murine haemopoietic stem cells, assayed as spleen colony-forming units (CFU-S), has been determined after in vitro irradiation under well defined conditions with small numbers (0.15-3) of alpha-particles of incident energy 3.3 MeV (LET 121 ke V microns-1). Exponential survival curves were obtained with inactivation dose coefficients of 1.83 +/- 0.11 and 1.63 +/- 0.06 Gy-1 for 8 and 12-day CFU-S, respectively, corresponding to inactivation cross sections of 35.6 +/- 2.1 and 31.7 +/- 1.2 microns2. The results indicate that these radiosensitive stem cells have a significant probability of surviving the passage of a single alpha-particle track, estimated at 8 and 18% per particle passage, respectively, if the cells have a diameter of 7 microns. However, this estimation is strongly dependent on the assumed diameter. Conversely, it is demonstrated that the cells cannot have mean geometric diameters of less than 6.7 +/- 0.2 and 6.4 +/- 0.1 microns, respectively. Associated experiments have shown that some cells from the irradiated population do survive to form colonies that express delayed non-clonal chromosome aberrations.

Alpha Particles↗

PubMed2005

Prompt detection of alpha particles from 210Po: another clue to the origin of rock varnish?

Alpha particles have been measured coming from the surfaces of rocks covered with dark red-brown rock varnish, as well as rocks that appear to have little, if any, varnish. A pronounced peak at 5.3 MeV indicates the presence of 210Po, a short-lived natural-radioactive element. Surface activities for 33 samples range from 0.008 Bq/cm2 to 0.065 Bq/cm2. It is estimated that this nuclide is concentrated 10(11) times in these paper-thin coatings above its concentration in ground-level air. Gamma rays from the decay of 137Cs, a product of testing nuclear weapons some 50 years ago, were also detected. Analysis of samples of varnish stripped from the rock revealed traces of 239,240Pu and 238Pu. The presence of all of these isotopes strongly supports the theory that varnish films derive their building blocks from the atmosphere and, with time, all rocks in arid environments will become coated.

Alpha Particles↗

PubMed1980

[Alpha particle excited X-ray fluorescence analysis for trace elements in cervical spinal cords of amyotrophic lateral sclerosis (author's transl)].

The mean contents of trace elements in anterior gray horn section of cervical spinal cords of six amyotrophic lateral sclerosis (ALS) cases were relatively determined against those of six control cases by alpha-particle excited X-ray fluorescence analysis. The anterior gray horn section of cervical spinal cord samples were excited by 1.6 MeV alpha-particle beam of 2 mm diameter accelerated with a Van de Graaff accelerator, and characteristic X-ray spectra were measured with alpha Si(Li) detector. From the peak area on the X-ray spectra, the relative mean contents of the trace elements in cervical spinal cords of ALS and control cases were determined. As a result, the X-ray peaks of Al, Si, P, S, Cl, K, Ca, Ti, V, Mn, Fe, Cu and Zn were detected. The contents of Al, Si, P, Ca, Ti, V, Mn and Fe in ALS cases were higher than those in control cases. The contents of S, Cl, K, Cu and Zn in ALS and control cases were equal to each other within standard deviation. The precipitation mechanisms of Al, Si, P, Ca, Ti, V, Mn and Fe into cervical spinal cord of ALS cases are discussed on the basis of the previous studies.

Alpha Particles↗

PubMed2005

Bound PCNA in nuclei of primary rat tracheal epithelial cells after exposure to very low doses of plutonium-238 alpha particles.

Bystander effects from ionizing radiation have been detailed for a number of cell systems and a number of end points. We wished to use a cell culture/ex vivo rat model of respiratory tissue to determine whether a bystander effect detected in culture could also be shown in a tissue. Examination by immunofluorescence techniques of tracheal cell cultures after exposure to very low doses of alpha particles revealed a large proportion of cells with proliferating cell nuclear antigen (PCNA) bound in their nuclei. PCNA was selected as an end point because it is involved in both DNA repair and the changes in cell cycle that are typical of many reported bystander effects. Maximum response can be detected in up to 28% of the cells in sub-confluent cultures with a dose of only 2 mGy. At this dose less than 2% of the cell nuclei have experienced a particle traversal and less than 6% of the cells have experienced an alpha-particle traversal through either their nucleus or some part of their cytoplasm. The hypothesis that this bystander response in nontargeted cells is mediated through secreted factor(s) is presented, and supporting evidence was found using partial irradiation and co-culture experiments. Examination of the effect with excised pieces of trachea demonstrated a response similar to that seen in culture.

Alpha Particles↗

PubMed1994

Cellular dosimetry: absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments.

UNLABELLED: The importance of cellular dosimetry in both diagnostic and therapeutic nuclear medicine is becoming increasingly recognized. METHODS: Experimental range-energy relations for electrons and alpha particles, along with derived geometric reduction factors, are used to calculate cellular absorbed fractions for these radiations. The resulting absorbed fractions are employed to calculate cellular S-values for several radionuclides. RESULTS: Cellular absorbed fractions for monoenergetic electron sources with energies ranging from 0.1 keV to 1 MeV, distributed uniformly in the source region, are calculated for several target<--source combinations including cell<--cell, cell<--cell surface, nucleus<--nucleus, nucleus<--cytoplasm and nucleus<--cell surface. Similar data are also provided for monoenergetic alpha particle sources with energies ranging from 3 to 10 MeV. S-values are also conveniently tabulated for 32P, 35S, 86Rb, 89Sr, 90Y, 91Y, 114mIn, 131I. Auger-electron-emitters 51Cr, 67Ga, 99mTc, 111In, 123I, 125I, 201TI, 203Pb and the alpha emitter 210Po. In addition, S-values are given for radionuclides in the 212Pb decay series, including 212Pb, 212Bi and 212Po. Both absorbed fractions and S-values are supplied for a number of different size cells and cell nuclei. CONCLUSIONS: With the absorbed fractions and S-values in hand, along with experimentally determined information on the biokinetics and subcellular distribution of the radionuclides, the cellular self-absorbed dose can be conveniently calculated.

Alpha Particles↗

PubMed1996

Micronucleus induction in human lymphocytes: comparative effects of X rays, alpha particles, beta particles and neutrons and implications for biological dosimetry.

The cytokinesis-block micronucleus assay in peripheral blood lymphocytes has the potential for being a simple and rapid method of biological dosimetry. This technique has been used to study the induction of micronuclei in the blood from 12 donors after exposure to a range of radiations with track-averaged LET values ranging from 0.26 to 44 keV microns -1. Data based on the average response of the 12 individuals for 250 kVp X rays were found to agree well with results published previously from other laboratories using similar techniques. Low dose-limiting RBE values relative to 250 kVp X rays for the radiations studied were found to be 0.50 for strontium/yttrium-90 beta particles, 6.9 for 20-23 keV microns -1 alpha particles and 17 for 24 keV neutrons. The pattern of the variation of individual radiosensitivity was found to be complex and dependent on dose, and the evaluation of individual radiosensitivity based on the response at one dose only can be misleading. It is concluded that, although the cytokinesis-block micronucleus assay in blood lymphocytes is a radiobiologically appropriate technique to use for biological dosimetry, its practical implementation may be limited by a need to perform individual pre-exposure calibrations.

Adult↗

PubMed2001

High-level production of alpha-particle-emitting (211)At and preparation of (211)At-labeled antibodies for clinical use.

UNLABELLED: In vitro and in vivo studies in human glioma models suggest that the antitenascin monoclonal antibody 81C6 labeled with the 7.2-h-half-life alpha-particle emitter (211)At might be a valuable endoradiotherapeutic agent for the treatment of brain tumors. The purpose of this study was to develop methods for the production of high levels of (211)At and the radiosynthesis of clinically useful amounts of (211)At-labeled human/mouse chimeric 81C6 antibody. METHODS: (211)At was produced through the (209)Bi(alpha, 2n)(211)At reaction using an internal target system and purified by a dry distillation process. Antibody labeling was accomplished by first synthesizing N-succinimidyl 3-[(211)At]astatobenzoate from the corresponding tri-n-butyl tin precursor and reacting it with the antibody in pH 8.5 borate buffer. Quality control procedures consisted of methanol precipitation, size-exclusion high-performance liquid chromatography (HPLC), and pyrogen and sterility assays, as well as determination of the immunoreactive fraction by a rapid procedure using a recombinant tenascin fragment coupled to magnetic beads. RESULTS: A total of 16 antibody labeling runs were performed. Using beam currents of 50-60 microA alpha-particles and irradiation times of 1.5-4.5 h, the mean (211)At production yield was 27.75 +/- 2.59 MBq/microA.h, and the maximum level of (211)At produced was 6.59 GBq after a 4-h irradiation at 55 microA. The decay-corrected distillation yield was 67% +/- 16%. The yield for the coupling of the (211)At-labeled active ester to the antibody was 76% +/- 8%. The fraction of (211)At activity that eluted with a retention time corresponding to intact IgG on HPLC was 96.0% +/- 2.5%. All preparations had a pyrogen level of <0.125 EU/mL and were determined to be sterile. The mean immunoreactive fraction for these 16 preparations was 83.3% +/- 5.3%. Radiolysis did not interfere with labeling chemistry or the quality of the labeled antibody product. CONCLUSION: These results show that it is feasible to produce clinically relevant activities of (211)At-labeled antibodies and have permitted the initiation of a phase I trial of (211)At-labeled chimeric 81C6 administered directly into the tumor resection cavities of brain tumor patients.

Alpha Particles↗

PubMedDate not supplied

Effects of the alpha-particle emitter At-211 and low-dose-rate gamma-radiation on the human cell line Colo-205 as studied with a growth assay.

BACKGROUND: The aim of this study was to investigate the biological effect of the alpha-particle-emitting isotope astatine-211 on the human cell line Colo-205 and to compare it with that of low-dose-rate gamma-radiation. MATERIALS AND METHODS: Plastic (PMMA) rotating phantoms were constructed, allowing precise dosimetry on a cellular level for both types of radiation. Growth assays using 96-well plates were used to estimate apparent cell survival for the two types of radiation. From this, the relative biological effect (RBE) could be estimated. RESULTS: Irradiation of the cells with 211At resulted in an RBE of 25.1 +/- 6.7 at 37% survival, and 17.3 +/- 2.5 at 10% survival, when compared with low-dose-rate gamma-irradiation. The absorbed dose at 37% survival, 0.12 Gy, corresponds to 2.2 traversals of alpha-particles through the cell nuclei. For cells irradiated with gamma-radiation (1 and 2 Gy), an apparent cell survival above unity was observed up to 50 hours post-irradiation, indicating a possible radiation hormesis effect. CONCLUSIONS: The RBE of 211At found in this growth-assay study was significantly higher than previously presented values. The difference might be due to the use of low-dose-rate gamma-radiation as reference. The RBE presented here could prove valuable when evaluating 211At-labelled compounds for radiotherapy.

Alpha Particles↗

PubMed1988

212Bismuth linked to an antipancreatic carcinoma antibody: model for alpha-particle-emitter radioimmunotherapy.

For comparison of cytotoxicity from alpha-particle irradiation with that from conventional x-irradiation, 212Bi, an alpha-emitting radionuclide, was attached to a monoclonal antibody that recognizes a cell surface antigen on human pancreatic carcinoma cells. For a given level of survival, the 212Bi-antibody complex was found to be approximately 20 times more efficient in cell killing than x-irradiation and 5 times more cytotoxic when compared with the cytotoxicity of an antigen-negative cell line or an isotype-matched control antibody. High linear energy transfer radioimmunotherapy using alpha emitters linked to monoclonal antibodies may be useful in vivo and in vitro for selectively killing target cell populations, especially those resistant to other forms of treatment.

Antibodies, Monoclonal↗

PubMed1997

p53 gene mutation analysis in tumors of patients exposed to alpha-particles.

The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations.

Aged↗

PubMed2002

Quality factors for alpha particles emitted in tissue.

A concept of a mean or dose averaged quality factor was defined in ICRP Publication 26 using relationships for quality factor as a function of LET. The concept of radiation weighting factors, wR, was introduced in ICRP Publication 60 in 1990. These are meant to be generalized factors that modify absorbed dose to reflect the risk of stochastic effects as a function of the quality of the radiation incident on the body or emitted by radioactivity within the body. The values of wr are equal to 20 for all alpha particles externally or internally emitted. This note compares the dose averaged quality factor for alpha particles originating in tissue using the old and revised recommendations for quality factor as a function of LET. The dose averaged quality factor never exceeds 20 using the old recommendations and is never less than 20 with the revised recommendations.

Alpha Particles↗

PubMed1997

Alpha-particle-induced neoplastic transformation in synchronized hybrid cells of HeLa and human skin fibroblasts.

Survival and oncogenic transformation frequencies were determined through the cell cycle in hybrid cells (HeLa x human skin fibroblasts), exposed to 0.30 and 0.15 Gy 4.3 MeV (LET= 101 keV/microm) alpha-particles. The cells were synchronized by mitotic collection and irradiated at times ranging from 2 to 10 h after collection, corresponding to G1 and early S. At 0.30 Gy the highest value in the transformation frequency (1.6 +/- 0.3) x 10(-4) transformants/survivor, occurred 4 h after mitotic collection, corresponding to mid-G1 and was about twice as high as that for the asynchronous population (0.7 +/- 0.1) x 10(-4) transformants/survivor. A similar pattern was seen at 0.15 Gy albeit less marked. The results are similar to previous findings with C3H10T1/2 exposed to 0.30 Gy where (1.8 +/- 0.4) x 10(-4) and (0.8 +/- 0.4) x 10(-4) transformants/survivor were found in mid-G1 and in the asynchronous population respectively. The results of both these studies with 101 keV/microm alpha particles indicate that mid-G1 cells may be more sensitive than asynchronous cells by up to a factor of two. However, it is unlikely that such a factor is sufficient to represent the cell cycle 'hot spot' for transformation postulated to explain the inverse dose-rate effect.

Alpha Particles↗