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PubMed2002

Quantification of radiation induced DNA double-strand breaks in human fibroblasts by PFGE: testing the applicability of random breakage models.

PURPOSE: To assess the applicability of methods of quantification of double-strand breaks (DSB) based on the random breakage paradigm, measuring yield and distribution of DSB induced by varying radiation quality. MATERIAL AND METHODS: 240 kVp X-rays and (238)Pu alpha-particles were used to induce DSB in AG01522B primary human fibroblasts. DNA molecular weight distributions were resolved by means of three pulsed-field gel-electrophoresis (PFGE) protocols, which, when combined together, allowed separation and quantification of double-stranded fragments between 5.7 Mbp and 12 kbp. Several analytical methods quantified the DSB yields. RESULTS: Data showed significant differences in the fragmentation patterns according to radiation quality. For both X-rays and alpha-particles, it was observed that the shape of the fragmentation profiles deviates from the prediction of a random breakage mechanism. This is in contrast to other studies where sparsely ionizing radiations appeared to distribute breaks uniformly throughout the genome. Deviations from random breakage were more evident after high linear energy transfer (LET) radiation, which showed an excess of breaks <1 Mbp and a deficit in the production of fragments >1 Mbp, a value that could be dose-dependent. CONCLUSIONS: Current methods of DNA fragmentation analysis after induction of DSB may lead to contradictory conclusions on both DSB yields and distributions. This study showed that the application of different DSB quantification methods, derived from random breakage or supported by its concepts, resulted in different radiation biological effectivenesses (RBE) for the induction of DSB, depending on how these methods were employed. To compare experimental results from different laboratories, care should be taken to provide as many details as possible about the application of methods of quantification of DNA damage. For all the methods used, total DSB yields resulted in RBE less than those for mutation induction or reproductive cell death, suggesting that total DSB yields only gave a limited indication of the severity of the inflicted damage. Production of correlated breaks on the chromatin loop structures by single particle-track traversals may explain the deviations observed between experimental data and the predictions of the random breakage paradigm.

Alpha Particles↗

PubMed2005

Efforts to control the errant products of a targeted in vivo generator.

Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P < 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P < 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P < 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.

Actinium↗

PubMed1998

Manifestations and mechanisms of radiation-induced genomic instability in V-79 Chinese hamster cells.

PURPOSE: The relationship between different forms of persistent radiation damage in irradiated cells was investigated in order to identify a common underlying mechanism. MATERIAL AND METHODS: V-79 Chinese hamster cells were irradiated with different doses of X-rays, neutrons and alpha-particles. In the progeny of surviving cells, up to 4 weeks after irradiation, delayed reproductive death, delayed micronuclei, delayed appearance of dicentric chromosomes and delayed apoptosis were investigated in parallel. RESULTS: A similar dose-response relationship was found for all endpoints, with a steep rise at low doses to a plateau at doses > 3 Gy. The target for inducing genomic instability by alpha-particles is larger than the nucleus. All chromosomes are equally involved in delayed breakage reunion events. CONCLUSION: The results indicate that non-lethal radiation damage to an extranuclear target leads to a persistent increase in clastogenic activity in the surviving irradiated cells.

Alpha Particles↗

PubMed2001

Molecular alterations in tumorigenic human bronchial and breast epithelial cells induced by high LET radiation.

Carcinogenesis is a multi-stage process with sequence of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer. In the present study, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells were irradiated with graded doses of either 150 keV/micrometer alpha particles or 1 GeV/nucleon 56Fe ions. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. The differential expressions of known genes between tumorigenic bronchial and breast cells induced by alpha particles and their respective control cultures were compared using cDNA expression array. Among the 11 genes identified to be differentially expressed in BEP2D cells, three (DCC, DNA-PK and p21(CIP1)) were shown to be consistently down-regulated by 2 to 4 fold in all the 5 tumor cell lines examined. In contrast, their expressions in the fusion cell lines were comparable to control BEP2D cells. Similarly, expression levels of a series of genes were found to be altered in a step-wise manner among tumorigenic MCF-10F cells. The results are highly suggestive that functional alterations of these genes may be causally related to the carcinogenic process.

Alpha Particles↗

PubMed1980

Synthesis of inducible enzymes in irradiated yeast cells: inhibition by ionizing radiation.

The induced activity of the enzyme arginase was measured in diploid wild type Saccharomyces cerevisiae after X-ray and 241Am-alpha-particle exposure. It was found that after doses which are comparable to those necessary to reduce survival, little effect on enzyme activity is seen immediately after irradiation but it is reduced on further incubation. In this case there is an oxygen enhancement ratio of about 2 as for survival. Suppression immediately after exposure requires considerably higher doses, and no oxygen effect is seen. To achieve the same effect with alpha-particles requires even higher doses, the apparent r.b.e. is about 0 . 1. X-ray damage to induced enzyme activity is subject to liquid holding recovery. The results are discussed in relation to current theories of gene inactivation by ionizing radiation.

Alpha Particles↗

PubMed1984

Flow cytometric determination of radiation-induced chromosome damage and its correlation with cell survival.

Chinese hamster M3-1 cells were irradiated with several doses of X rays or alpha particles from 238Pu. Propidium iodide-stained chromosome suspensions were prepared at different times after irradiation; cells were also assayed for survival. The DNA histograms of these chromosomes showed increased background counts with increased doses of radiation. This increase in background was cell-cycle dependent and was correlated with cell survival. The correlation between radiation-induced chromosome damage and cell survival was the same for X rays and alpha particles. Data are presented which indicate that flow cytometric analysis of chromosomes of irradiated cell populations can be a useful adjunct to classical cytogenic analysis of irradiation-induced chromosomal damage by virtue of its ability to express and measure chromosomal damage not seen by classical cytogenic methods.

Alpha Particles↗

PubMed2003

Determination of the 8B neutrino spectrum.

We have measured the total energy of the alpha particles following the beta decay of 8B by implanting 8B into a planar silicon surface barrier detector. Calibration was performed using alpha particles following the beta decay of 20Na, similarly implanted. The alpha spectrum is used to infer the 8B neutrino spectrum which is an important input in the interpretation of experiments that detect energetic neutrinos from the Sun. The alpha spectrum reported here is in disagreement with the previous best measurement which used two detectors in coincidence.

Journal Article↗

PubMed1993

Track studies in water vapor using a low-pressure cloud chamber. I. Macroscopic measurements.

Techniques have been developed to operate a low-pressure cloud chamber with pure water vapor. Photographs have been obtained of the tracks arising in this medium from the passage of ionizing radiation. The sources used were low-energy X rays, 242Cm alpha particles, and low-energy protons. Track lengths of the electrons were similar to those found previously in tissue-equivalent gas. W values of 35.6 +/- 0.4 and 32.6 +/- 0.6 eV per ion pair for carbon and aluminum X rays also compare closely with those in tissue-equivalent gas, but are somewhat higher than the predictions of Monte Carlo calculations. Differential w values were obtained: for alpha particles of energy 5.3 MeV the value was 33.0 +/- 3.0 eV per ion pair; for protons of energy 390, 230, and 85 keV the values were 30.6 +/- 1.9, 31.9 +/- 2.0, and 33.6 +/- 3.4 eV per ion pair. The energy losses of protons in water vapor were measured in a second (dummy) chamber used for energy calibration. Results support Janni's values of stopping power for protons in the energy range 40-480 keV.

Alpha Particles↗

PubMed2002

In vitro radiation-induced effects on rat tracheal epithelial cells. II) Different preneoplastic cell transformation after alpha and gamma irradiations.

In order to compare the cell transformation induced by alpha- and gamma-irradiation, primary cultures of tracheal epithelial cells from two rat strains, Sprague Dawley (SD) and Wistar Furth/Fisher F344 (WF/Fi) rats, were irradiated with 241Am alpha-particles or 60 Co gamma-rays. The relative transformation frequency (RTF) for WF/Fi primary cells was very close to the level of the spontaneous incidence and independent on the two irradiation types used. On the contrary, the RTF for the SD primary cells increased with a decrease of the LET radiation when the relative survival was higher than about 40%. Therefore, the RTF values reached 4-5 for alpha-particles and 10-12 for gamma-rays. The RTF can be related to the intrinsic radiosensitivity of the rat epithelial cells. However, the difference in the radiation-induced RTF for SD or WF/Fi primary cells seems to be due to the development, under genetic control, of the initial lesion to the neoplastic state.

Alpha Particles↗

PubMed2002

A new perspective of carcinogenesis from protracted high-LET radiation arises from the two-stage clonal expansion model.

When applied to the Colorado Plateau miner population, the two-stage clonal expansion (TSCE) model of radiation carcinogenesis predicts that radiation-induced promotion dominates radiation-induced initiation. Thus, according to the model, at least for alpha-particle radiation from inhaled radon daughters, lung cancer induction over long periods of protracted irradiation appears to be dominated by radiation-induced modification of the proliferation kinetics of already-initiated cells rather than by direct radiation-induced initiation (i.e., mutation) of normal cells. We explore the possible consequences of this result for radiation exposures to space travelers on long missions. Still unknown is the LET dependence of this effect. Speculations of the cause of this phenomenon include the suggestion that modification of cell kinetics is caused by a "bystander" effect, i.e., the traversal of normal cells by alpha particles, followed by the signaling of these cells to nearby initiated cells which then modify their proliferation kinetics.

Alpha Particles↗

PubMed1997

Is there reliable experimental evidence for a chromosomal "fingerprint" of exposure to densely ionizing radiation?

A selection of published data on the ratio, F, of interchromosomal to intrachromosomal stable (reciprocal translocations and pericentric inversions) and unstable (dicentric chromosomes and centric rings) exchange aberrations in human lymphocytes has recently been presented as evidence for F values of about 15 for X and gamma rays and about 6 for neutrons and alpha particles (D. J. Brenner and R. K. Sachs, Radiat. Res. 140, 134-142, 1994). On this basis it was proposed that low F values could serve as a chromosomal "fingerprint" of densely ionizing radiation. In the present commentary it is shown that some of the quoted data sets provide little support for this concept. It is further demonstrated that our own data, including a "head-to-head" experiment with gamma rays and alpha particles, reveal no LET dependence, even in the comparison of F values from low-LET radiation with those from low doses of high-LET radiation. In this context it is pointed out that a change in F values cannot be expected at doses of high-LET radiation where the linear component of the dose-effect relationship for exchange aberrations prevails. Additional data for the effects of high- and low-LET radiation which have not been considered in the discussion so far confirm that support of the concept of F-ratio "fingerprinting" by experimental data is insufficient.

Alpha Particles↗

PubMed2003

Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal.

Cerebral angiography using a radioactive radiological contrast medium, Thorotrast, was pioneered by Moniz in Portugal in the 1920s. Thorotrast is retained by the reticuloendothelial system, with a biological half-life of several hundred years, so that such patients suffer lifetime exposure to internal radiation. We studied mortality in Portuguese patients who were administered Thorotrast during the period 1928-1959 and in a comparison group of patients who received nonradioactive contrast agents. There were 1096 systemically exposed, 1014 unexposed, and, unique to the Portuguese study, 240 locally exposed Thorotrast patients who were successfully traced and followed up to the end of 1996. Mortality was significantly raised among systemically exposed Thorotrast patients relative to those unexposed for all causes [relative risk (RR) = 2.63], all neoplasms (RR = 6.72), liver cancer (RR = 42.4), chronic liver disease (RR = 5.12), other non-neoplastic diseases of the digestive system (RR = 4.87), neoplastic (RR = 21.9) and non-neoplastic hematological disorders (RR = 6.00), and non-neoplastic diseases of the respiratory system (RR = 4.31). Risks for most of these conditions increased significantly with time since first administration of the contrast medium and with cumulative alpha-particle radiation dose. Mortality was also significantly raised for non-neoplastic disorders of the nervous system (RR = 12.7) and ill-defined conditions (RR = 3.74), but these associations are likely to reflect the initial diagnosis, not Thorotrast exposure, because risks declined significantly with time and/or dose. There were no significant excess deaths from oropharyngeal or nasal cancers, or from any other cause, among patients exposed to Thorotrast locally for visualization of the perinasal sinuses, and no clear trend in risk with time since exposure. This study shows an association between systemic, but not local, exposure to Thorotrast and mortality from liver cancer, chronic liver disease, and neoplastic and non-neoplastic hematological disorders, with risks for these conditions remaining high for over 40 years after administration. Liver conditions, but not hematological disorders, showed a strong and consistent gradient with cumulative alpha-particle radiation dose.

Adolescent↗

PubMed1989

Measurement of the G-value for 1.5 keV X-rays.

Although there are several theoretical predictions of the dependence of the G-value on X-ray energy, measurements have not been made below approximately equal to 7 keV. Using a ferrous sulfate solution modified by the addition of benzoic acid, we have measured the relative G-values for Alk characteristic X-rays (1.5 keV), 238Pu alpha-particles (3.7 MeV), 60Co (1.17 MeV) and 137Cs (0.66 MeV) gamma-rays. This modified ferrous sulfate solution gave a 4-fold increase in sensitivity relative to the conventional solution, making measurements with the Alk X-rays feasible. The relative ferrous-to-ferric conversions as a function of dose were similar for the two gamma-ray energies, yielding G-values of 1.62 and 1.59 mumol J-1 for the 60Co and 137Cs radiations, respectively. The alpha-particle G-value was 0.52 mumol J-1, or 31 per cent of that for the 60Co gamma-rays, in good agreement with previous measurements. The Alk X-rays had a G-value of 0.92 mumol J-1 or 57 per cent of that of the 60Co radiation. This G-value for the 1.5 keV X-rays is within 20 per cent of the values predicted by current theories, and theoretical values are within the error range of our measurement. The consistency between the experimental value reported here and theoretical G-values for ultrasoft X-rays should be valuable for models of radiation action on biological systems.

Alpha Particles↗

PubMed1996

Radiosensitivity of haplont yeast cells irradiated with sparsely and densely ionizing radiations.

Five haploid and three diploid yeast strains of various species (Yarrowia lipolytica, Pichia pinus and Pichia guilliermondii) were irradiated with alpha-particles from 239Pu and gamma-rays from 137Cs or 60Co in the stationary phase of growth. A common feature of these species is that they exhibit a haploid state as a normal vegetative state in natural conditions. It was shown that the transition from the haploid to the diploid state is not accompanied by increased radioresistance, and diploid strains were unable to perform liquid-holding recovery. The absence of diploid-specific recovery in diploid strains was also supported by the fact that the RBE of alpha-particles was almost identical for haploid and the corresponding diploid strains being much smaller than that observed in typical wild-type diploid strains capable of diploid-specific recovery. The results suggest that haplont yeast may have evolved to diplont yeast via the development of a specific repair system conferring specific resistance in the diploid state.

Alpha Particles↗

PubMed1988

His+ reversions caused in Salmonella typhimurium by different types of ionizing radiation.

The yield of his+ reversions in the Ames Salmonella tester strain TA2638 has been determined for 60Co gamma rays, 140 kV X rays, 5.4 keV characteristic X rays, 2.2 MeV protons, 3.1 MeV alpha particles, and 18 MeV/U Fe ions. Inactivation studies were performed with the same radiations. For both mutation and inactivation, the maximum effectiveness per unit absorbed dose was obtained for the characteristic X rays, which have a dose averaged linear energy transfer (LET) of roughly 10 keV/micron. The ratio of the effectiveness of this radiation to gamma rays was 2 for inactivation and about 1.4 for the his+ reversion. For both end points the effectiveness decreases substantially at high LET, i.e., for the alpha particles and the Fe ions. The composition of the bottom and the top agar was the one recommended by Maron and Ames [Mutat. Res. 113, 173-215 (1983)] for application in chemical mutagenicity tests. The experiments with the less penetrating radiations differed from the usual protocol by utilization of a technique of plating the bacteria on the surface of the top agar. As in an earlier study [Roos et al., Radiat. Res. 104, 102-108 (1985)] greatly enhanced yields of mutations, relative to the spontaneous reversion rate, were obtained in these experiments by performing the irradiations 6 h after plating, which differs from the conventional procedure to irradiate the bacteria shortly after plating.

Alpha Particles↗

PubMed1990

Radiation-induced cell transformation: transformation efficiencies of different types of ionizing radiation and molecular changes in radiation transformants and tumor cell lines.

This study aims to compare the efficiencies of 5.4 keV soft X-rays, alpha-particles, and gamma-rays in transforming C3H 10T1/2 cells and to assess the sequence of cellular and molecular changes during the process of radiation-induced transformation of Syrian hamster embryo (SHE) cells. The somewhat more densely ionizing soft X-rays are more effective than gamma-rays both for cell inactivation and cell transformation. The relative biological effectiveness (RBE) appears to be independent of dose; it is approximately 1.3 for either end point. The RBE of alpha-particles versus gamma-rays, on the other hand, increases with decreasing dose; the dose dependence is somewhat more apparent for cell transformation than for cell inactivation. SHE cells transformed by different types of ionizing radiation and related tumor cell lines isolated from nude mice tumors were found to have a distinct growth advantage compared to primary SHE cells, documented by higher plating efficiencies, shorter doubling times, and higher cloning efficiencies in semisolid medium. Most transformed and tumor cell lines that were investigated have elevated mRNA levels for the H-ras gene, some of them show restriction fragment length polymorphisms of the H-ras gene, and some exhibit a substantially amplified c-myc gene. In a sequence analysis of the Syrian hamster H-ras gene of eight tumor cell lines from radiation transformants, we have not found any mutation in codons 12, 13, 59, 61, nor in the flanking regions of these codons. The transformed and tumor cell lines tend to have lower chromosome numbers than primary SHE cells.

Alpha Particles↗

PubMed2005

Microdosimetry of inhomogeneous radon progeny distributions in bronchial airways.

A Monte Carlo code, initially developed for the calculation of microdosimetric spectra for alpha particles in cylindrical airways, has been extended to allow the computation (i) of additional microdosimetric parameters and (ii) for realistic exposure conditions in human bronchial airways with respect to surface activity distribution and airway geometry. The objective of the present study was to investigate the effects of non-uniform distributions of radon progeny activities in bronchial airways on cellular energy deposition parameters. Significant variations of hit frequencies, doses and microscopic energy deposition patterns were observed for epithelial cell nuclei, depending strongly on the assumed activity distributions. Thus, epithelial cells located at different positions in a given bronchial airway may experience a wide range of biological responses. The results obtained suggest that the hit frequency may be the primary physical parameter for alpha particles, supplemented by microdosimetric single event spectra, to be related to biological effects for chronic low level exposures.

Administration, Inhalation↗

PubMed2002

Involvement of membrane signaling in the bystander effect in irradiated cells.

We have shown previously that when confluent cultures of mammalian cells are exposed to very low fluences of alpha particles, fluences whereby only 1-3% of the cell nuclei are traversed by a particle, genetic effects, including specific gene mutations and sister chromatid exchanges, are induced in neighboring, nonirradiated ("bystander") cells (H. Nagasawa and J. B. Little, Cancer Res., 52: 6394-6396, 1992; H. Nagasawa and J. B. Little, Radiat. Res., 152: 552-557, 1999). The present experiments were designed to determine whether signaling pathways arising in the cell membrane may mediate this effect. Cells were irradiated in the presence of Filipin, an agent that disrupts lipid rafts, effectively inhibiting membrane signaling, and the induction of sister chromatid exchange and HPRT mutations by very low fluences of alpha particles (mean doses 0.17-0.5 cGy) was measured. Filipin completely suppressed the induction of both genetic effects in bystander cells. After exposure to 10 cGy, when most mutations occurred in directly irradiated cells, no suppressive effect of Filipin was observed. These results suggest that membrane signaling may play an important role in the bystander effect of radiation. On the other hand, the effects in directly irradiated cells do not appear to be mediated via the cell membrane.

Alpha Particles↗