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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↗

PubMed1993

Mechanisms of radiosensitization in bromodeoxyuridine-substituted cells.

The radiosensitization of exponentially-growing V79-171 cells whose DNA has been substituted by bromodeoxyuridine (BrdU) in place of thymidine is decreased if acetone is present during irradiation. Acetone, at a concentration of 1 mol dm-3, removes the majority of the increase in double-strand breaks (dsbs) caused by BrdU substitution, but only removes approximately half of the increase in cell killing. The decrease in cell radiosensitization coincides with the removal of the additional dsbs. The protection afforded by acetone against dsbs is assumed to be due to its ability to scavenge hydrated electrons, thought to be the active species causing the increased DNA damage in the presence of BrdU. The residual component of BrdU radiosensitization which could not be removed by treatment with acetone may be due to either a subset of nonscavengable, lethal dsbs or the influence of BrdU on the fixation of potentially-lethal damage (Iliakis et al. 1992). Cells substituted with BrdU are not sensitized to hydroxyl radicals (from hydrogen peroxide). Also, the enhanced levels of single-strand break (ssb) and dsb production in cells substituted with BrdU arise from analogous events (i.e. increases in the yield of ssbs). These studies support the locally multiply damaged site theory of lesion (dsb) production (Ward 1981) and, in the case of BrdU-substituted cells, the increase in dsbs appears to be due to the production of additional ssbs by hydrated electrons at sites of multiple damage.

Acetone↗

PubMed1993

Radiation-induced DNA damage and repair in radiosensitive and radioresistant human tumour cells measured by field inversion gel electrophoresis.

Radiation-induced DNA damage induction and repair was measured in two human squamous carcinoma cell lines with differing radiosensitive. Experiments were carried out with field inversion gel electrophoresis (FIGE), adapted to measure DNA double strand break (DSB) induction and repair in unlabelled cells. The sensitivity of the method was increased by introducing a hybridization membrane into the agarose gel. Damaged DNA accumulated on one spot on the membrane resulting in high local concentrations. This DNA was quantified using radioactively-labelled total human DNA as a probe. Dose response experiments for damage induction correlated well with the results using prelabelled cells. Linear DNA damage induction curves were observed with a sensitivity for the post-labelling method of 1 Gy. No differences in DSB induction were found, however, between the radiosensitive SCC61 and the radioresistant SQ20B cell line. Repair experiments were carried out with trypsinized cells with different doses and repair temperatures. The 10, 25 and 50 Gy doses resulted in 6, 13 and 50% of the DNA migrating out of the plug at 0 h. For both the cell lines 75-85% of the initial damage was repaired within 1 h at 37 degrees C at all three radiation doses, i.e. no significant differences were observed in repair rates or extent between the two cell lines. At 24 degrees C repair was slower than at 37 degrees C, and at 0 degree C no repair was observed. In summary, radiosensitivity differences at physiological temperatures could not be explained by differences in either induction or repair of DNA damage as measured by pulsed field gel electrophoresis.

Carcinoma, Squamous Cell↗

PubMed1994

The female guinea pig, a useful model for the genetic hazard of radiation in man; preliminary results on germ cell radiosensitivity in foetal, neonatal and adult animals.

A comparison was made of the radiosensitivities of the resting oocyte of guinea pig in its two different states, the 'large' resting and 'contracted' oocyte, also extending the investigations to the radiosensitivity of the female germ cells at earlier stages during intrauterine life. The radiosensitivity of guinea pig oocytes was evaluated by testing the fertility of the animals 6 months and 1 year after irradiation of the ovaries with high doses (2 or 4 Gy) of X-rays. Animals had been treated in utero (target cells: oogonia and oocytes at leptotene), at birth (target cells; resting oocytes of the large type) or as adults (target cells: resting oocytes of the contracted type). No loss of fertility was evident, even 1 year after treatment, whatever the stage or dose. These investigations were completed by histological studies of the ovaries from treated and control animals. Irradiation induced a dose-dependent decrease in the total number of oocytes, and this effect was more pronounced in animals irradiated as adults (target cells: contracted resting oocytes). Our results also suggested that the LD50 of the large guinea pig resting oocyte should be around 4 Gy, a value similar to that obtained recently for the equivalent human oocyte. This confirms the high radioresistance of the guinea pig oocyte and the consequence suitability of this species for further detailed studies in relation to genetic hazards in man.

Animals↗

PubMed1996

Chromatin structure and cellular radiosensitivity: a comparison of two human tumour cell lines.

The role of variation in susceptibility to DNA damage induction was studied as a determinant for cellular radiosensitivity. Comparison of the radiosensitive HX142 and radioresistant RT112 cell lines previously revealed higher susceptibility to X-ray-induced DNA damage in the sensitive cell line using non-denaturing elution, but not when using alkaline unwinding. The present data also show that no difference in the amount of initial damage is seen when pulsed-field gel electrophoresis (PFGE) or comet analysis are used for DNA damage assessment. However, using the halo assay or a modified version of PFGE in which the higher DNA architecture remained partially intact, the radiosensitive cells showed steeper dose-response curves for initial DNA damage than the radioresistant cells. Analysis of the protein composition, of DNA-nucleoid structures revealed substantial differences when isolated from HX142 or RT112 cells. From our data, it is concluded that HX142 and RT112 differ in their structural organization of chromatin. As no differences in the kinetics of DNA damage rejoining were found, it is hypothesized that the same amount of lesions have a different impact in the two cell lines in that the 'presentation' of DNA damage alters the ratio of repairable to non-repairable DNA damage.

Chromatin↗

PubMed1996

An interaction of cisplatin and radiation in two rat yolk sac tumour cell lines with different radiosensitivities in vitro.

We investigated the interaction of cisplatin and radiation in two rat yolk sac tumour cell lines with different radiosensitivities in vitro. The effects were assessed by clonogenic assay. D0 for the radiosensitivity of the radioresistant variant cell line, NMT-1R was 139 cGy, which was 1.3 times larger than that for the parent radiosensitive cell line, NMT-1 (D0 = 107 cGy). The concentration of cisplatin required to reduce colony formation by 50% at 1 h treatment (ID50 of cisplatin) was 0.25 microgram/ml for NMT-1, whereas that for NMT-1R was 1.0 microgram/ml. Cisplatin potentiation of radiation sensitivity was manifested by the decrease in the slope of the radiation dose-response curve. D0's for NMT-1 and NMT-1R were 83 and 100 cGy in combined treatment with ID50 of cisplatin immediately before radiation. The enhancement ratios of cisplatin were therefore 1.30 for NMT-1 and 1.39 for NMT-1R respectively in D0. No different enhancement ratio for cisplatin was observed in the time course of combination treatment with cisplatin and radiation within the interval of 6 h. There was no clear change in cell cycle distribution within 6 h after treatment with ID50 of cisplatin for both cell lines. In conclusion, cisplatin had a synergistic effect on both cell lines which was independent of the time course and sequence in combination with radiation within 6 h.

Animals↗

PubMed1996

Low dose-rate fibroblast radiosensitivity and the prediction of patient response to radiotherapy.

The relationship between cellular radiosensitivity and normal-tissue response to radiotherapy in individual cancer patients has attracted increasing attention over the last few years. Recent work has suggested that a correlation exists between fibroblast sensitivity and normal-tissue reactions. We have examined the radiosensitivity of fibroblasts grown from skin biopsies of four normal individuals and three patients identified as having suffered unexpectedly severe reactions to clinical radiotherapy, called here 'over-reactor' (OR) patients. Clonogenic survival was measured after high (HDR) and low dose-rate (LDR) irradiation. By comparing the two, and LDR Recovery Factor was derived. Potentially-lethal damage repair was examined in 4 cell strains. After HDR the OR strains were indistinguishable from the normals. At LDR the range of sensitivity was expanded. The OR strains fell at the sensitive end of the range and were characterized by a lack of LDR recovery, which clearly distinguished them from the normal strains. Experimental errors were estimated by considering all the data sets together rather than viewing each experiment individually. Duplicate strains from several patients were tested, and the differences between them were found to be within the estimated experimental errors, suggesting that these differences were not biologically significant. The data are consistent with the hypothesis that normal-tissue response is linked to individual cellular radiosensitivity. Our data confirm the importance of using LDR irradiation in clinical investigations of cellular sensitivity.

Adult↗

PubMed1997

G2 chromosomal radiosensitivity in fibroblasts of ataxia-telangiectasia heterozygotes and a Li-Fraumeni syndrome patient with radioresistant cells.

PURPOSE: To investigate whether the good discrimination we previously observed between ataxia-telangiectasia (A-T) heterozygotes and normal donors for induction of chromosome aberrations by X-rays in G2 lymphocytes is also seen in G2 fibroblasts. Also to investigate the G2 radiosensitivity of a patient with the cancer-prone Li-Fraumeni syndrome (LFS) whose fibroblasts are resistant to the lethal effects of radiation. MATERIALS AND METHODS: Fibroblasts were exposed to 0.5 Gy X-rays and harvested for metaphase analysis 90 min later. RESULTS: Four A-T heterozygote cell strains were all more sensitive than seven normal controls. The LFS strain with a germline TP53 mutation was twice as sensitive as the mean control value. CONCLUSIONS: Although chromosomal, radiosensitivity is seen in A-T heterozygotes and LFS cells, the former are radiosensitive and the latter radioresistant to cell killing. Repair defects may predominate in A-T heterozygotes, inadequate genome surveillance in LFS cells.

Ataxia Telangiectasia↗

PubMed1997

Correlation between slowly repairable double-strand breaks and thermal radiosensitization in the human HeLa S3 cell line.

The effect of heat on double-strand breaks (dsb) repair was compared with thermal radiosensitization using HeLa S3 cells. Cells were exposed to a combined treatment of X-irradiation followed by heat (44 degrees C, 0.5 h) separated by time intervals up to 8 h. DNA dsb were measured by PFGE and survival by the colony forming assay. In non-heated HeLa S3 cells repair of dsb was biphasic with the majority of breaks being repaired fast with a half-time of 14 min and only a minority were repaired slowly with a half-time of 130 min. Heat applied immediately after irradiation was found to cause an increase in both half-times but mainly to result in an increased fraction of slowly repairable dsb. The latter effect was shown to result from the formation of additional dsb. The number of additional dsb declined when irradiation and heat were separated by an interval at 37 degrees C with a half-time of 120 +/- 30 min. This half-time was similar to the half-time of 100 +/- 20 min found for the loss of thermal radiosensitization studied for the same protocol. Both processes were recently found also to correlate in CHO cells but occurred much faster in rodent cells than in the human HeLa S3 cells used in the current study. These results show that in human cells, unlike previously suggested on the basis of rodent cells, thermal radiosensitization is still a substantial contributor to the killing efficacy of a combined treatment even when irradiation and heat are separated by a time internal of 4 h.

Cell Survival↗

PubMed1997

Enhanced radiosensitivity by inhibition of nuclear factor kappa B activation in human malignant glioma cells.

To clarify the relationship between cellular radiosensitivity and nuclear factor kappa B (NF-kappa B) activation, an expression plasmid was constructed for I kappa B-alpha, a cellular inhibitory protein of NF-kappa B, and transfected it into two human malignant glioma cell lines. Cells overexpressing the I kappa B-alpha protein were more radiosensitive than the parental cells and one transfected clone with low expression. In the parental cell lines and one transfected clone with low expression, the sequence specific DNA-binding activity of NF-kappa B was considerably increased between 1 and 2 h after irradiation. In contrast, no increase in the DNA-binding activity was observed in the transfected clone overexpressing I kappa B-alpha protein. These results suggest that the activation of NF-kappa B may be one of the intrinsic responses determining cellular radiosensitivity.

Clone Cells↗

PubMed1997

Resistance to heat radiosensitization and protein damage in thermotolerant and thermoresistant cells.

Recently, randomized phase III trials have indicated that hyperthermia combined with radiation leads to significantly better tumour control of certain malignancies than does radio-therapy alone. Yet, the full capacity of such combined treatments might not have been optimally exploited as in vitro data indicate that repeated beating of cells can result in either the development of a transient heat resistance (thermotolerance) and/or the selection/induction of a stable heat resistant cell population. Although the mechanism of thermotolerance and its effect on thermo-radiotherapy has been studied extensively, little data are available on the mechanism of stable heat resistance and its impact on combined heat and radiation treatments. In the current study, a comprehensive analysis was made of the differences and similarities between thermotolerance (TT) and stable heat resistance (TR) in terms of the mechanism of resistance to the direct toxic action of heat and in terms of the impact on the extent of thermal radiosensitization. Using heat resistant mutants previously derived from a murine radiation-induced fibrosarcoma (RIF-1), it was observed that these cells were resistant to protein denaturation and aggregation in the cytoplasmic/membrane compartment (measured by ESR (electron spin resonance) analysis and by in situ thermal denaturation of the foreign firefly luciferase targeted to the cytoplasm) but not in the nuclear compartment (measured by TX-100 insoluble nuclear proteins and by in situ thermal denaturation of luciferase targeted to the nucleus). RIF-1-TT cells, in contrast, were resistant for a 1 end-points tested. The lack of protection of nuclear heat damage in the RIF-TR cells could not be explained by a failure of one or more of the HSP70 isoforms to enter the nuclei of these cells. In relation to the absence or presence of heat resistance in the nucleus, the extent of heat radiosensitization was reduced in RIF-1-TT but not RIF-TR cells. This implies that resistance for heat killing is not necessarily accompanied by a reduction in the ability of heat to enhance the cellular radiosensitivity. The data indicate that the mechanism leading to permanent resistance after repeated heating and the mechanism causing thermotolerance may share common features but are in part different.

Animals↗

PubMed1998

Lack of correlation between ATM protein expression and tumour cell radiosensitivity.

PURPOSE: Cells derived from individuals in which the ataxia telangiectasia (ATM) gene is mutated are hypersensitive to ionizing radiation. Whether differences in ATM protein levels exist among human malignant glioma cell lines and whether such differences are correlated with cellular radiosensitivity were determined. MATERIALS AND METHODS: Polyclonal antibodies were raised to separate regions of the ATM protein. ATM protein expression in human malignant glioma cell lines, SV40 transformed normal human fibroblasts and SV40 transformed AT fibroblasts was analysed by Western blotting. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the presence of ATM transcript. RESULTS: While ATM protein was detected in all cell extracts, significant differences in the level of expression were observed. There was no apparent correlation between cellular radiosensitivity and differences in ATM protein levels in these human glioma cells. Extremely low levels of ATM protein were observed in M059J cells, which provide the only example of DNA-dependent protein kinase (DNA-PKcs) deficiency in a cell line of human origin. CONCLUSIONS: Variations in the levels of ATM protein are insufficient to explain the differences in cellular radiosensitivity observed in a panel of human malignant glioma cell lines.

Ataxia Telangiectasia↗

PubMed1998

Further characterization of the radiosensitivity of the scid mouse.

PURPOSE: To further characterize the radiation response of the scid mutation. MATERIALS AND METHODS: X-ray induced chromosomal aberrations and cell killing were analysed using various in vivo or in vitro cell systems. RESULTS: Using low LET X-irradiation a reverse dose-rate effect was found for killing of differentiated and differentiating spermatogonia and the chromosomal hyperradiosensitivity of scid mice was extended to the meiotic prophase. Most striking was the observation made in vitro with synchronized established cell lines that, contrary to the situation in wild-type cells, scid cells display high levels of both chromatid- and chromosome type aberrations when irradiated during the G1-phase of the cell cycle. A time-course for induction of micronucleated polychromatic erythrocytes (MPCE) was determined for scid mice using flow analysis. No significant differences with wild-type mice were recorded. The chromosomal radiosensitivity at the G1 stage in scid cells was 4.3 times higher than in control CB-17 cells whereas G2 sensitivity differed only by a factor of 1.3. CONCLUSIONS: The reportedly normal radiosensitivity for MPCE in scid mice together with previous findings of hypo- or normal radiation sensitivity of scid cells could be explained by the induction of highly lethal chromatid-type damage at the G1 stage of the cell cycle leading to selective elimination of aberration-carrying cells. The differences in chromosomal radiosensitivity between wild-type and scid for the G1 and G2 stage of the cell cycle correlate with variation in the rates of DNA double-strand break (dsb) repair in scid cells during the cell cycle found by others.

Animals↗

PubMed1998

Radiosensitivity of normal fibroblasts from breast cancer patients assessed by the micronucleus and colony assays.

PURPOSE: To investigate whether radiation-induced micronucleus formation as expressed by the cytochalasin-blocked Mn-assay correlates with cellular radiosensitivity measured by a colony assay in primary fibroblast cultures from cancer patients. MATERIALS AND METHODS: Studies were made on skin fibroblasts from 36 breast cancer patients. The micronucleus assay was performed using treatment with cytochalasin-B to create binucleate cells. Response was scored in terms of the percentage of binucleate cells with micronuclei, also as the number of micronuclei per binucleate cell. The data were related to previously published results of cell survival measurements on these cell lines. RESULTS: Neither endpoint for micronucleus formation showed a correlation with radiosensitivity by the colony assay. The fraction of fibroblasts that reach mitosis without micronuclei also failed to correlate with cell survival. CONCLUSIONS: Among these primary fibroblast cell lines radiation-induced micronucleus formation was not associated with radiosensitivity as measured by a colony assay.

Adult↗

PubMed1998

Radiosensitivity as support for the structure of a unimolecular DNA quadruplex.

PURPOSE: To search for possible variations of radiosensitivity along a unimolecular DNA quadruplex and to use them as support for choosing one of the two possible structures proposed by NMR studies. MATERIALS AND METHODS: The probability of radiation-induced frank strand breaks (FSB) and of alkali-revealed breaks (ARB) at each nucleotide site along the oligomer AATTCGTGGAGCACC (T4G4)4, was determined by sequencing gel electrophoresis as has been previously described in the literature. The oligomer was irradiated as a unimolecular quadruplex (QS) or paired to its complementary oligonucleotide in a double-stranded B-helix (DS). RESULTS: The oligomer globally presents the same radiosensitivity in the quadruplex or in the double-stranded helix. FSB occur with the same probability at each nucleotide site in both QS- and DS-DNA. More ARB are induced at T- and less at G-sites in QS-DNA. The probability of ARB induction in the second T-run is lower than in the first and the third one. CONCLUSION: Intrastrand radiosensitivity variations support the folding of the studied oligomer into a quadruplex with two lateral loops and one central loop of T-runs spanning the diagonal of the terminal G-quartet.

Circular Dichroism↗

PubMed1999

p53 status, cellular recovery and cell cycle arrest as prognosticators of in vitro radiosensitivity in human pancreatic adenocarcinoma cell lines.

PURPOSE: To investigate the factors contributing to the in vitro radiosensitivity of four human pancreatic adenocarcinoma cell lines differing in p53 status, and the basis for the lack of post-irradiation G1 arrest in the two cell lines that have retained a wild-type p53 allele. MATERIALS AND METHODS: Cells were X-irradiated and the parameters related to radiosensitivity, as well as the modulation of gene products linked to regulation of cell cycle transit (p53, p21/WAF1/CIP1, pRb) or DNA replication and repair (DNA topoisomerase I and II), were determined. RESULTS: Both cell lines expressing either mutant (mt) R248W or R273H p53 proteins were more radioresistant. All the cell lines arrested in G2. None of the cell lines arrested in G1 and this was linked to the inability to upregulate p21/WAF1/CIP1. There were no correlations between p53 status and the magnitude or time of maximum G2 arrest. However, there was a negative correlation between a protracted arrest in G2 and the ability to recover from potentially lethal damage (PLD). CONCLUSIONS: Variation in radiosensitivity is related to p53 status, but the survival advantage conferred by having mutant p53 status is not readily explained neither by recovery from PLD nor by cell cycle arrest kinetics. There is no p53-independent pathway for the recruitment of p21 in these cell lines following irradiation.

Adenocarcinoma↗

PubMed1999

Potential of radiation-induced chromosome aberrations to predict radiosensitivity in human tumour cells.

PURPOSE: To validate whether the number of aberrations could be used as a measure of the radiosensitivity of human tumour cells. If so, this would potentially provide a more rapid method than the colony assay to predict radiocurability in human tumour biopsy material. MATERIALS AND METHODS: A panel of 13 human tumour cell lines was investigated, covering a wide range of radiosensitivities. Fluorescence in situ hybridization (FISH) employing whole chromosome probes was used to detect aberrations. RESULTS: A dose-dependent increase in radiation-induced chromosome aberrations was observed in all cell lines. A good correlation (r=0.90) was found between cell survival and total chromosome aberrations in 12 of the 13 cell lines (92%), with one exception. A poorer correlation was observed between cell survival and stable- (r=0.85) and unstable-type aberrations (r=0.81). Survival-aberration correlations for individual radiation doses were worse, although statistically significant. The exceptional cell line showed significantly more aberrations for a given level of cell kill than expected based on data for the other lines. CONCLUSION: This study indicates that radiation-induced chromosome aberrations can be used as a potential predictor of intrinsic radiosensitivity for the majority of human tumours when more than one dose level is tested. This could aid the design of radiotherapy schedules for each individual patient, or in the decision of whether to use an alternative therapy.

Cell Survival↗

PubMed1999

Increased chromosomal radiosensitivity in breast cancer patients: a comparison of two assays.

PURPOSE: It has been shown previously that sensitivity to the induction of chromosome damage by ionizing radiation is, on average, higher in G2 or G0 lymphocytes of breast cancer patients than of normal healthy controls. The authors suggested that elevated chromosomal radiosensitivity may be a marker for breast cancer predisposition. To investigate whether the G0 micronucleus assay is a true surrogate for the more demanding G2 metaphase assay, both tests have now been performed on the same blood samples from 80 patients. METHODS: For the G0 micronucleus assay, cells were exposed to 3.5 Gy 137Cs gamma-rays 6 h before mitogenic stimulation, treated with cytochalasin B at 24 h post-stimulation and harvested at 90 h. For the G2 assay, at 72 h after stimulation cells were given 0.5 Gy X-rays and harvested 90 min later. RESULTS: Previous observations were confirmed, now with much larger numbers of donors, in that approximately 40% of breast cancer patients showed elevated sensitivity in the G2 assay (135 patients, 105 normals) and 25% in the G0 assay (130 patients, 68 normals). However, there was no correlation between G2 and G0 sensitivity for the 80 patients tested (r = -0.001, p = 0.99). Most of the sensitive patients were either G2 or G0 sensitive, with only 4% sensitive in both assays. CONCLUSIONS: The results suggest that different mechanisms of chromosomal radiosensitivity operate in G2 and G0 cells and that, in general, each chromosomally radiosensitive patient is defective in only one such mechanism, possibly via mutation (or polymorphism) of a single gene. Such mutations may confer cancer predisposition, of low penetrance, in a substantial proportion of patients.

Adult↗