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PubMed1975

The relationship between chromosome aberrations and low LET radiation dose to human lymphocytes.

In vitro dose-response curves of unstable chromosome aberrations in human lymphocytes have been obtained for 250 kV X-rays and cobalt-60gamma-radiation. The aberration yields have been fitted to the quadratic function Y = alphaD +betaD2, which is consistent with the single-track and two-track model for aberration formation. The values of the coefficients alpha and beta support the hypothesis that the dose-rate effect is limited to the D2 term. The main difference between the coefficients for X- and gamma-radiation is in the alpha values, indicating that X-rays are slightly more efficient, at lower doses, in producing two lesions with a single ionizing track. The lower limits of dose estimate, with 500 cells analysed, are 4 rad for X-rays and 10 rad gamma-radiation. Further evidence is presented confirming that, for cytogenetic dosimetry, in vitro dose-response curves should be prepared by irradiating whole blood maintained at 37 degrees C and prior to PHA stimulation. Curves were plotted showing the variation of the number of cells without aberrations with radiation dose and the shape of these curves were compared with those from human cell survival experiments.

Adult↗
PubMed1985

The influence of dose rate on the lethal and mutagenic effects of X-rays in proliferating L5178Y cells differing in radiation sensitivity.

The lethal and mutagenic effects of ionizing radiation delivered at high (53 Gy/h) and low (0.02 Gy/h) dose rates were measured in two closely related strains of mouse lymphoma L5178Y cells differing in radiation sensitivity (LY-R and LY-S). Strain LY-R was more resistant to the lethal effects of radiation than strain LY-S when exposed at either the high or low dose rate. The survival of strain LY-R was markedly enhanced by the reduction in dose rate. The dose-rate dependence of the survival of strain LY-S was less clear, because of the biphasic nature of its survival curve following low dose-rate radiation. However, if the initial slope of the low dose-rate survival curve is compared to the slope of the high dose-rate survival curve for strain LY-S, only a slight increase in survival at the low dose rate is apparent. Although more sensitive to the lethal effects of radiation, strain LY-S was less mutable at the hypoxanthine/guanine phosphoribosyl transferase locus by both low dose-rate and high dose-rate radiation than strain LY-R. Little dose-rate dependence was exhibited by either strain with regard to the mutagenic effects of radiation. Thus, for strain LY-R, which showed marked dose-rate dependence for survival but not for mutation, the ratio of mutational to lethal lesions was much greater following exposure to low dose-rate than to high dose-rate radiation.

Animals↗
PubMed1986

UV-type damage associated with ionizing radiation: a review.

The induction of UV-type damage by ionizing radiation in repair deficient strains of E. coli is reviewed. Both photoreactivable and non-photoreactivable types of damage can be observed. The induction of UV-type damage is largely independent of the presence of free-radical reactive agents (e.g. oxygen and thiols), but is dependent upon the energy of the photon--or electron--beam used, the radiation geometry and the optical absorbance of the extracellular medium. On the basis of calculations and experimental evidence, it is clear that one mechanism whereby such damage arises is through the generation of Cerenkov emission. However, small yields of UV-type damage can be produced using X-rays whose energy is below the threshold for production of Cerenkov emission. In this instance, the damage induction mechanism is thought to involve a direct excitation process.

Absorption↗
PubMed1989

Stable radioresistance in ataxia-telangiectasia cells containing DNA from normal human cells.

SV40-transformed ataxia-telangiectasia (AT) cells were transfected with a cosmid that contains a normal human DNA library and a selectable marker, the neo gene, which endows successfully transformed mammalian cells with resistance to the antibiotic G418. After a three-part selection protocol for G418 resistance and radioresistance, a cell line stably resistant to ionizing radiation was recovered. Cells from this line were irradiated with 50 Gy of X-rays and fused with non-transfected AT cells. Among the G418-resistant colonies recovered was one that was stably resistant to radiation. Resistance to ionizing radiation of both the primary transfectant line and its fusion derivative was intermediate between that of AT cells and normal cells, as assayed by colony-forming ability and measurement of radiation-induced G2 chromatid aberrations; both cell lines retained AT-like radioresistant DNA synthesis. These results suggest that, because radioresistance in the transfected cells was not as great as that in normal human cells, the two hallmarks of AT, radiosensitivity and radioresistant DNA synthesis, may still be the result of a single defective AT gene.

Ataxia Telangiectasia↗
PubMed1989

Increased radiosensitivity and the basic defect in ataxia telangiectasia.

Various cellular defects have been found in ataxia telangiectasia (A-T) cells including increased radiosensitivity, increased sensitivity to various chemical agents, a probable DNA repair defect and a defect in DNA synthesis. How these different features are related to each other is at present unknown. It has been suggested that there is a defect in A-T that acts in tissue differentiation as well as during growth and in the mature adult. This hypothesis is supported by the observations, for example, of an immature thymus present in patients, the production of alpha-fetoprotein, which results in a high serum level, and ovarian dysgenesis. A gene for A-T has recently been localized to chromosome region 11q22-23, a site involved in chromosomes translocations in some non-lymphoid leukaemias. At the chromosomal level the spontaneous abnormalities in A-T include, first, an increased frequency of cells showing chromosome translocations involving immune system genes that normally undergo rearrangement to form a functional product; secondly, the formation of telometric dicentrics in both lymphocytes and fibroblasts; and thirdly formation of long-lived chromosome damage following exposure to ionizing radiation and radiomimetic drugs. The gene defect underlying this disorder is unknown and distinguishing between primary and secondary effects of the mutant gene is difficult. We consider alternative models for retention of translocation T cells. First, it is possible that there is a defect in recognition of site-specific damage leading to retention of translocation cells that might otherwise be removed. Secondly, a feature common to the production of illegitimate T-cell receptor gene rearrangements and to formation of telomeric dicentric chromosomes in A-T cells is an increased period of time available for chromosome interchange, possibly due to a site-specific defect in strand break repair. It is possible that this defect may also prevent chromosome restitution following exposure of cells to ionizing radiation.

Ataxia Telangiectasia↗
PubMed1992

Extracellular DNA level in the blood of irradiated rats.

There is high-molecular DNA in the blood of unirradiated rats which moves as a single fraction during electrophoresis in 0.5% agarose. At short times (2-5 h) after gamma-irradiation at doses from 1 to 100 Gy a low-molecular species of DNA appears (about 180 nucleotide pairs), the amount of which is directly proportional to exposure dose at 5 h after exposure. It has been established by Southern hybridization that the low-molecular DNA has few nucleotide sequences common with those of the high-molecular DNA, but it shows homologously to genomic sequences.

Animals↗
PubMed1992

Lack of differential G2 chromosomal radiosensitivity between non-tumorigenic and tumorigenic human hybrid cells (HeLa x skin fibroblasts).

Previous studies have shown, that for log phase cultures, tumorigenic segregants of HeLa x skin fibroblast human hybrid cells are slightly more radiosensitive in terms of cell killing than their nontumorigenic parents (Redpath et al. 1985, Colman et al. 1988). Other studies have shown that these same tumorigenic segregants exhibit a markedly enhanced G2 chromosomal radiosensitivity (Sanford et al. 1986) thus offering a possible explanation for the cell killing data. The present study set out to examine the G2-phase radiosensitivity of these cells in terms of cell killing with the expectation that an enhanced sensitivity in the tumorigenic cells would be seen. No enhanced sensitivity was observed. The G2 chromosomal radiosensitivity was then examined and no differential was seen between the non-tumorigenic and tumorigenic cells. This lack of confirmation of previously reported studies may be due to some technical differences in the experimental protocols.

Cell Line, Transformed↗
PubMed1993

Relationships between DNA damage and the survival of radiosensitive mutant Chinese hamster cell lines exposed to gamma-radiation: Part 2. Effect of cellular redox status.

To characterize further the nature of the defects underlying the differential radiosensitivities of the Chinese hamster ovary cell lines NM2, EM9, and UV41, we compared the abilities of anoxia and of the thiol WR-1065 to protect these mutants and their parent cell line, AA8, from the lethal effects of gamma-radiation. Wide differences in oxygen enhancement ratios (OERs) for cell killing were observed in the different cell lines, those for UV41 and NM2 cells (1.8 and 2.1, respectively) being reduced and that for EM9 cells (3.3) being slightly (although significantly) increased compared with wild-type AA8 cells (2.9). These OER data support the hypothesis that repair-deficient mutants are hypersensitive to radiation under redox conditions that favour the formation of the particular lesions that correspond to their repair defect, and also support the earlier suggestion that the underlying molecular bases of the radiosensitivity of EM9 and NM2 cells are very different. In contrast to protection by anoxia, a 30-min preirradiation treatment with WR-1065 (4 mmol dm-3) protected aerated AA8, EM9, NM2, and UV41 cells to a similar extent with respect to both cell killing and the efficiency of DNA double-strand break (dsb) induction as measured by neutral elution. This observation is in marked contrast with reports of a greatly reduced protection by thiols for some repair-deficient cell lines and with the above-mentioned anoxia data. Thus, the particular types of mutations characteristic of NM2, EM9, and UV41 cells that give rise to their unusual OERs have little impact on the ability of WR-1065 to modify either cell killing or dsb induction, supporting radiochemical evidence that the types of deoxyribose radicals modifiable by oxygen and thiols are qualitatively different. Furthermore, because the extent of protection of these CHO mutants by thiols and anoxia show no correlation, oxygen depletion cannot be a major component of protection of aerated cells by thiols under these conditions.

Animals↗
PubMed1993

Onset of chromatin fragmentation in chloroma cell apoptosis is highly sensitive to UV and begins at non-B DNA conformation.

UV irradiation induces programmed death, or apoptosis, in rat chloroleukaemia cells, a process characterized by typical cell morphology, fragmentation of chromatin into units of single and multiple nucleosomes, and transcriptional activation of LINE. Our study shows that this process is initiated by very low UV doses: exposure to one minimal erythema dose (MED, about 200 J/m2), at defined wavelengths ranging from 270 to 330 nm, is sufficient. By sequencing 100 randomly selected blunt-end chromatin fragments (single and multiple nucleosomes) we observed that at an early stage of apoptosis the fragmented DNA contains a four-fold excess of both long and short interspersed nuclear retroelements (LINEs and SINEs). A distinct sequence finding was also the observation that fragmented DNA is very rich in microsatellites, (CA)n dinucleotides in particular, and in long stretches of homopurine/homopyrimidine domains. The present results thus indicate that chromatin fragmentation in UV-induced apoptosis begins at non-random locations involving non-B DNA conformation, and that the onset of the suicide process in chloroleukaemia cells is surprisingly sensitive to UV exposure.

Animals↗
PubMed1993

Effects of extended low-dose-rate exposure to 137Cs detected by flow-cytometric enumeration of micronucleated erythrocytes in mouse peripheral blood.

An automated variant the of micronucleus assay for erythrocytes in mouse peripheral blood has recently been developed. The flow-cytometric technique used allows very large numbers of erythrocytes to be analysed with a relatively small effort. Here we report the potential of this method to detect a response to extended low-dose-rate exposure to gamma-irradiation. The mice were irradiated with a 137Cs source at a dose rate of 4.8 cGy/day for 26 days. Sampling was continued for another 39 days after irradiation. Elevated frequencies compared with the control group were found at days 2, 9 and 20 after the start of the irradiation for micronucleated polychromatic erythrocytes, and at days 9, 20, 29, 42, 51 and 65 for micronucleated normochromatic erythrocytes.

Animals↗
PubMed1993

Mechanisms of oxygen radiosensitization in irradiated yeast. I. DNA double-strand breakage.

The relative contributions of the OH-mediated and direct radiation effect on the induction of DNA double-strand breaks (dsbs) were evaluated in two haploid yeast cell lines (GSH+ and gsh-) irradiated under oxic or hypoxic conditions in the absence or presence of 6 M glycerol as an OH radical scavenger. Gsh- cells are deficient in glutathione (GSH) biosynthesis, their GSH content is only 2% compared with GSH+ cells. Similar relative contributions are observed for both cell lines. Under oxic irradiation conditions about 64% of the response can be attributed to the OH-mediated (or indirect) radiation effect, whereas in hypoxic cells the indirect effect is only about 45%. High oxygen enhancement ratios (OERs) are observed for the OH-mediated radiation effect (4.24 for GSH+, 2.70 for gsh- cells) and low OERs for the direct effect (1.66 for GSH+, 1.44 for gsh- cells). The weighted total (i.e. direct and indirect) OER is 2.74 (GSH+) and 2.03 (gsh-). The dependence of radiosensitization for double-strand breakage on oxygen concentration is characterized by three components whose K-values are 0.5, 4 and 20% oxygen for GSH+ cells and 0.45, 5 and 60% oxygen for gsh- cells. Evidence is presented that the first two components represent the radiosensitization by oxygen of the OH-mediated effect, whereas the third component, requiring the highest oxygen concentration for sensitization, represents the radiosensitization by the direct effect. GSH+ and gsh- cells show virtually the same K-values for the OH-mediated effect, but different K-values for the direct effect.

DNA Damage↗