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PubMedDate not supplied

[Effect of inhibitors of DNA synthesis on the sensitivity of mammalian cells to radiation with different levels of linear energy transfer].

Radiosensitivity of Chinese hamster cells increased by 1.71 times in the presence of arabinoside cytosine and hydroxyurea after gamma-irradiation, and no sensitization occurred after irradiation with carbon ions of 6.6 MeV/nuclon (LET, 227 keV/micron). Under a standard set of conditions, the RBE coefficient of carbon ions decreased from 3.09 to 1.78 in the presence of DNA synthesis inhibitors. The possible mechanism of this phenomenon is discussed.

Animals↗
PubMed1981

[Effect of radiations with varying linear energy transfer on the skin of mice].

Experiments were carried out to measure the time and severity of the radiation reaction of the skin of mice exposed to X- and gamma-radiations, protons with energies of 645 and 50 MeV as well as accelerated helium ions at doses of 200 to 4000 rad. It was found that relative biological effectiveness coefficients of 645 and 50 MeV protons were 1.0 and those of helium ions were 1.3 for the skin reaction at early and late stages of observation. No significant difference in the time of manifestation of radiation-induced skin lesions as related to radiations with various LET was detected.

Animals↗
PubMed1994

Initial damage in human interphase chromosomes from alpha particles with linear energy transfers relevant to radon exposure.

To determine the efficiency at which alpha particles at LETs chosen to simulate exposure to radon progeny break chromosomes, the premature chromosome condensation technique was used to measure breaks soon after irradiation. Noncycling human fibroblasts were irradiated with graded doses of monoenergetic alpha particles accelerated to produce LETs of 90, 120, 150, 180 and 200 keV/microns at the midpoint of the cell nuclei. Premature chromosome condensation was initiated immediately after irradiation and cells were scored for the total number of prematurely condensed chromosomes and fragments per cell. Similar experiments were conducted with 250 kVp X rays for comparison. Irradiation with alpha particles produced 8.6 to 13.1 excess fragments per gray, while X rays produced 5.8 excess fragments, resulting in RBEs around 2. Calculations of the number of breaks produced on average by a single particle traversal of a cell nucleus indicated that at the LETs tested more than one break (1.5-2.8) was produced by each traversal, the maximum being that produced by 180 keV/microns alpha particles. When chromosome aberrations are scored at metaphase after high-LET irradiation, RBEs considerably greater than those recorded here (approximately 2) have been reported. These results showing relatively small differences in initial break levels for alpha particles in the LET range of the radon progeny relative to X rays indicate that the greater aberration frequencies are not due principally to an increase in breakage efficiency, but interactions between breaks along the same particle track are important.

Alpha Particles↗
PubMed1994

The response of Chinese hamster V79-379A cells exposed to negative pi-mesons: evidence that increased radioresistance is dependent on linear energy transfer.

Chinese hamster V79-379A cells exhibit low-dose hypersensitivity to 250 kVp X rays followed by an increased radioresistant response over the dose range 0.5-1 Gy. This phenomenon is not seen with neutrons (Marples and Joiner, Radiat. Res. 133, 41-51, 1993). It was therefore postulated the induction of radioresistance might develop as a response to a cellular event(s) which predominates after low- and not high-LET radiation. To test this hypothesis, we measured the survival response of V79-379A cells exposed to pions. Clonogenic survival was assessed for cells irradiated in the Bragg peak (35 keV/microns) and plateau region (10-20 keV/microns) of the beam, using an automated microscope (DMIPS cell analyzer). As expected, peak pions were found to be more effective per unit of dose at killing cells than plateau pions. The survival curve for cells irradiated in the plateau of the pion beam was found to incorporate a region of low-dose hypersensitivity and increased radioresistance, the effective D0 was dose-dependent, ranging from 3.5-5. This was not seen with peak pions, where the effective D0 was, on average, constant reflecting a single-exponential survival curve. Fitting the data with an induced repair model indicates that the phenomenon of increased radioresistance is almost certainly dependent on LET.

Animals↗
PubMed1993

Cancer mortality (1956-1985) among male employees of Atomic Energy of Canada Limited with respect to occupational exposure to external low-linear-energy-transfer ionizing radiation.

The mortality experience between 1956 and 1985 of 8977 males employed by Atomic Energy of Canada Limited is reported. A total of 4260 men, 47% of the cohort, were exposed to low doses of external ionizing radiation at low dose rates, with a mean cumulative equivalent dose of 52.1 mSv. For cancers as a whole the excess relative risk, based on 227 deaths, was 0.36% per 10 mSv (90% confidence bounds -0.46, 2.45). This is quite comparable to the corresponding estimate based on the atomic bomb survivors study. There was a positive association between radiation dose and death from leukemia (excluding chronic lymphatic leukemia) P = 0.058. However, this was based on only four deaths and hence cannot sensibly be compared to estimates based on high-dose studies. The present results suggest that, for cancer as a whole, risk estimates based on high-dose studies are unlikely to underestimate risks substantially for low-dose and low-dose-rate exposures.

Canada↗
PubMed2005

Different G2/M accumulation in M059J and M059K cells after exposure to DNA double-strand break-inducing agents.

PURPOSE: To investigate and compare the cell cycle progression in relation to cell death in the human glioma cell lines, M059J and M059K, after exposure to DNA double-strand break-inducing agents. METHODS AND MATERIALS: The M059J and M059K cells, deficient and proficient in the catalytic subunit of the DNA-dependent protein kinase, respectively, were exposed to 1 and 4 Gy of photons or accelerated nitrogen ions. In addition, M059J and M059K cells were treated with 10 and 40 mug/mL of bleomycin for 30 min, respectively. Cell cycle progression, monitored by DNA flow cytometry, was measured up to 72 h after treatment. RESULTS: M059J, but not M059K, cells displayed G(2)/M accumulation after low linear energy transfer irradiation. High linear energy transfer radiation exposure however, resulted in a substantial increase of M059K cells in the G(2)/M phase detected at 48 h. At 72 h, the number of cells in the G(2)/M phase was equivalent to its control. M059J cells accumulated mainly in S phase after high linear energy transfer irradiation. In contrast to M059K, M059J cells were still blocked at 72 h. Bleomycin induced G(2)/M accumulation for both M059J and M059K cells detected 24 h after treatment. At 48 h, the percentage of bleomycin-treated M059J cells in G(2)/M phase remained high, and the number of M059K cells had decreased to control levels. Neither cell line showed cell cycle arrest (< or =10 h) after exposure to these agents. CONCLUSION: Distinct cell cycle block and release is dependent on the complexity of the induced DNA damage and the presence of the DNA-dependent protein kinase catalytic subunit.

Antimetabolites, Antineoplastic↗
PubMed1995

Application of the HSEF to assessing radiation risks in the practice of radiation protection.

The primary risk coefficients upon which exposure limits for radiation protection purposes are currently based are derived almost exclusively from cancer-induction data obtained from human populations exposed to radiations of low linear energy transfer. The question of higher linear energy transfer radiations is handled by means of quality factors derived from values for relative biological effectiveness obtained from animal data. However, the advent of microdosimetry has made it possible to establish hit size effectiveness functions from single-cell systems, both in vitro and in vivo. This type of function can substitute completely for the concept of relative biological effectiveness, Q and equivalent dose. A common basis for risk coefficients and the hit size effectiveness function lies in the fact that human cancers are monoclonal and thus single cell in origin. The present communication utilizes this common base as a means of extending the present low-linear energy transfer based risk coefficients to include carcinogenic responses from exposure in radiation fields of any one or mixed qualities, extending from the smallest to the largest linear energy transfers of practical consequence. In doing so, risks from ionizing radiations of any linear energy transfer may be predicted more accurately than at present.

Biophysical Phenomena↗
PubMed2002

Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice.

Mutation rates at two expanded simple tandem repeat loci were studied in the germ line of first- and second-generation offspring of inbred male CBA/H, C57BL/6, and BALB/c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA/H exposure to either x-rays or fission neutrons resulted in increased mutation rates in the germ line of two subsequent generations. Comparable transgenerational effects were observed also in neutron-irradiated C57BL/6 and x-irradiated BALB/c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB/c>CBA/H>C57BL/6). Pre- and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA/H mice, which together with our previous results suggests that radiation-induced expanded simple tandem repeat instability is manifested in diploid cells after fertilization. The remarkable finding that radiation-induced germ-line instability persists for at least two generations raises important issues of risk evaluation in humans.

Alleles↗
PubMed2004

Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization.

PURPOSE: To evaluate by the fluorescent in-situ hybridization (FISH) technique the dose-response and intercellular distribution of alpha-particle-induced chromosome aberrations. In particular, the validity of using the yield of characteristic types of chromosome abnormalities in stable cells as quantitative indicators for retrospective dose reconstruction has been evaluated. MATERIAL AND METHODS: Monolayers of human peripheral lymphocytes were exposed at doses from 0.02 to 1 Gy to alpha-particles emitted from a source of americium-241. The most probable energy of the alpha-particles entering the cells was 2.7 MeV. FISH painting was performed using DNA probes for chromosomes 2, 4 and 8 in combination with a pan-centromeric probe. In complete first-division cells, identified by harlequin staining, aberrations involving painted target chromosomal material were recorded as well as aberrations involving only unpainted chromosomal material. RESULTS: In total, the percentage of complex aberrations was about 35% and no dose dependence was observed. When complex-type exchanges were reduced to simple base types, the different cell distributions were clearly over-dispersed, and the linear coefficients of the dose-effect curves for translocations were significantly higher than for dicentrics. For past dose reconstruction, only a few complex aberrations were in stable cells. The linear coefficient obtained for transmissible aberrations in stable cells was more than seven times lower than that obtained in all analysed cells, i.e. including unstable cells. CONCLUSION: FISH-based analysis of complex rearrangements allows discrimination between partial-body exposures to low-linear energy transfer radiation and high-linear energy transfer exposures. In assessing past or chronic exposure to alpha-particles, the use of a dose-effect curve obtained by FISH-based translocation data, which had not excluded data determined in unstable cells, would underestimate the dose. Insertions are ineffective biomarkers because their frequency is too low.

Adult↗
PubMed1976

Linear energy transfer-dependent radiosensitivity of Burkitt lymphoma cells, with special references to human melanoma HMV, HeLa-S3, and L5178Y cells.

Dependence of the survival curves of Burkitt lymphoma cells, which were featured by their small n or Dq values, on linear energy transfer (LET) obtained for different quality of radiation was revealed markedly in the change of D0 value, together with a small change in n value. Relative biological effectiveness (RBE) compared with Dq, n and D37 values of Burkitt lymphoma cells for high LET radiation was smaller than that of other cell lines. This finding supports the hypothesis that in Burkitt lymphoma cells the recovery capacity from sublethal damage (Dq) is so small even after low LET irradiation that LET does not modify the suppression of recovery. Similar survival curves with n value closely equal to 1 were obtained for four different mammalian cell lines (Burkitt lymphoma p3HR- 1, human melanoma HMV, HeLa-S3, and L5178Y) after 2 MeV neutron irradiation. This fact may suggest that the radiation which has an LET value at which n value of the survival curve is to be 1 will be optimum for therapeutic purpose to the radioresistant tumors.

Animals↗
PubMed1980

Stopping power and radial dose distribution for 42 MeV bromine ions.

Linear energy transfer restricted in radius (LETr) and total linear energy transfer (LET infinity) were determined for 42 MeV bromine ions in tissue-equivalent gas. A variable pressure cylindrical ionisation chamber was used. Dose as a function of distance from the ion's path was also determined using a mesh wall ionisation chamber placed inside the cylindrical chamber. The range of distances studied was from 5 to 710 A in simulated tissue of unit density. Experimentally obtained values of radial dose were compared with calculations made using Paretzke's program. Stopping power for these ions in tissue-equivalent gas was extrapolated from proton stopping power in constituent gases. In this calculation the effective charge of the ions was obtained from the formula given by Dimitriev and Nikolaev. This calculated value was 6.3 x 10(4) MeV g-1 cm2. The experimentally determined value was 7.3 x 10(4) MeV g-1 cm2. The discrepancy between calculated and experimental values may be due to uncertainty in the determination of the effective charge of the incident ions. Uncertainty on the experimental value of LET infinity was estimated to be +/- 5% (one standard deviation).

Bromine↗
PubMed1999

Studies on the red marrow dosimetry in radioimmunotherapy: an experimental investigation of factors influencing the radiation-induced myelotoxicity in therapy with beta-, Auger/conversion electron-, or alpha-emitters.

Usually, the red marrow (RM) is the first dose-limiting organ in radioimmunotherapy. However, several studies have obtained only poor correlations between the marrow doses and the resulting toxicities. Furthermore, RM doses are mostly not determined directly but are derived from blood doses by assuming a ratio that is, over time for the respective conjugates, more or less constant between blood and marrow activities. The aim of this study was to determine, in a mouse model, this RM:blood activity ratio for various immunoconjugates, to investigate whether there may be differences between complete IgG and its fragments with various labels ((125/131)I versus (111)In, (88/90)Y, or 213Bi), and to analyze, in more detail, factors other than just total dose, such as dose rate or relative biological effectiveness factors, that may influence the resulting myelotoxicity. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric, and humanized immunoconjugates as complete IgG or fragments (F(ab)2 and Fab), labeled with beta(-)-emitters (such as 131I or 90Y), Auger electron-emitters (such as 125I or (111)In), or alpha-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation was performed to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; besides the major organs, the activities in the blood and bone marrow (and bone) were determined over time. Whereas no significant differences were found for the RM:blood ratios between various IgG subtypes, different radiolabels or various time points, differences were found between IgG and bi- or monovalent fragments: typically, the RM:blood ratios were approximately 0.4 for IgG, 0.8 for F(ab')2, and 1.0 for Fab'. Nevertheless, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 microCi for IgG, 1200 microCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17, 9, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all three deliver approximately 4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for 90Y-conjugates. Higher RM doses were tolerated with Auger-emitters than with conventional beta(-)-emitters, whereas the MTDs were similar between alpha- and beta(-)-emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, two subsequent injections of two doses of 80% of the single shot MTA of 131I- or 90Y-labeled Fab' and two doses of 100% of the single shot MTA of 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart. In contrast, reinjection of bivalent conjugates was not possible within 6 weeks. These data suggest that the RM:blood activity ratios differ between IgG and fragments, although there is no anatomical or physiological explanation for this phenomenon at this point. In contrast to the current opinion, indication for a strong influence of the dose rate (or dose per unit time), not only total dose, on the resulting toxicity is provided, whereas the influence of high-linear energy transfer (alpha and Auger/conversion electrons) versus low-linear energy transfer (beta and gamma) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger-emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the RM.

Alpha Particles↗