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PubMed2003

Time factor for acute tissue reactions following fractionated irradiation: a balance between repopulation and enhanced radiosensitivity.

Experimental data for acute radiation-induced skin reactions are reviewed. These show that for dose fractionation schedules with gaps, repopulation is initiated after a lag period. After this lag period, the isoeffective dose for a given level of skin reaction first increases rapidly, but then slows. The timing of the lag period is related to the total turnover time of the tissue under investigation and, for example, is shorter in rodent skin than in pig or human skin. At the point when accelerated repopulation is initiated, there is a major shortening of the turnover time of the target cell population. At this time, there is evidence, for a short period, for an increase in radiosensitivity of the surviving stem cells in a number of acutely responding normal tissues. This effect is clearly illustrated by the results of experiments using sequential dose fractionation schedules. Prolongation of the schedule from 'short' to schedules that include irradiation over the period when the cell turnover is accelerated is associated with a marked increase in tissue radiosensitivity. Clinically, this is best illustrated by a comparison of the effects of accelerated fractionation schedules, involving multiple fractions/day, with daily fractionation schedules. The increase in radiosensitivity produced by the prolongation of the treatment from 2 to 4-5 weeks was equivalent to > or =1 Gy day(-1). Comparable findings were obtained from animal studies. In the oral mucosa of mice, the initiation of accelerated cell proliferation in surviving cells is associated with the loss of dose sparing by subsequent dose fractionation due to the loss of the capacity to repair sublethal damage. Studies in pig and human skin have indicated that increased radiosensitivity is associated with a loss of cells in the G1 phase of the cell cycle. A collation of these two sets of findings suggests that the repair of sublethal damage takes place over this phase of the cell cycle. One clinical implication of these findings is that the alpha/beta ratio for acute skin reaction changes with the length of the overall treatment time; it is approximately 4.0 Gy for 'short' fractionation schedules that avoid any shortening of the cell cycle time. This increases to 11.2-13.3 Gy for schedules given in 3-4 weeks and to approximately 35 Gy for schedules given in 5-6 weeks. Results for pig skin were in total agreement with those for human skin.

Animals↗

PubMed2005

Elevated G2 chromosomal radiosensitivity in Irish breast cancer patients: a comparison with other studies.

Previous studies have shown that a significant proportion of breast cancer patients exhibit elevated G2 chromosomal radiosensitivity in contrast to controls (approximately 40%). In this study, the G2 assay was applied to a small number of Irish breast cancer patients who were recorded as sporadic cases and they were compared with a control group to compare and contrast with the previous documented studies. Lymphocyte cultures were set up on whole blood samples and stimulated with phytohaemagglutinin. The cultures were irradiated 74 h later with 0.5 Gy gamma-radiation and cells were arrested in metaphase by treating the cultures with colcemid. The chromosomes were harvested and the aberrations scored per 100 metaphases to assign a G2 score. The assay was first carried out on four donor controls to estimate intra-individual variation and then ten controls for inter-individual variation to measure assay reproducibility. The G2 assay was then applied to 27 breast cancer patients. Good intrinsic assay reproducibility was observed in the coefficient of variation (CV) data in three out of four controls. Intra-individual variation was similar in three out of four of the donors (4.6 - 5.1%) with one donor showing a higher CV compared with the others (22.9%). Inter-individual variation was calculated at 30.5% for all controls. No significant difference was observed between intra- and inter-individual variation using the variance ratio F-test. A G2 radiosensitivity cut-off of 110 aberrations/100 metaphases was calculated from the controls, and from this 70.4% of breast cancer patients and 7.7% of controls were calculated as G2 radiosensitive. This proportion of G2-sensitive breast cancer patients is the highest recorded in studies to date. It is thought that the G2 radiosensitivity assay is a biomarker of breast cancer predisposition genes of low penetrance, suggesting the presence of these genes in the Irish breast cancer patients used in this study who were recorded as sporadic cases. A larger number of Irish patients would be required to consolidate these findings and be representative of the Irish breast cancer population.

Adult↗

PubMed2005

Attenuation of chronic thermotolerance by KNK437, a benzylidene lactam compound, enhances thermal radiosensitization in mild temperature hyperthermia combined with low dose-rate irradiation.

PURPOSE: We investigated whether the attenuation of chronic thermotolerance by KNK437, a heat shock protein inhibitor, can modify the effect of thermal radiosensitization in mild temperature hyperthermia (MTH) combined with low dose-rate irradiation (LDRI). MATERIALS AND METHODS: The human lung adenocarcinoma cell line A549 was simultaneously exposed to LDRI with MTH at 41 degrees C and KNK437 at a dose of 100 microM. Cell survival was estimated by a clonogenic assay. Cell cycle change during treatment was analyzed by flow cytometry. Expression levels of the heat shock proteins hsp72, hsp27 and heat shock factor 1 (HSF-1) were measured by Western blotting. RESULTS: KNK437 inhibited the expression of inducible hsp72 and hsp27, but produced no change in the mobility shift of HSF-1. The cytotoxicity of LDRI was enhanced by MTH. The survival curve for LDRI + MTH revealed no development of chronic thermotolerance up to 48 h. Simultaneous LDRI and KNK437 treatment also resulted in enhanced cell killing. The radiosensitizing effect of KNK437 was enhanced by simultaneous exposure of the cells to MTH. Flow cytometry analysis of cell cycle progression demonstrated marked G2 arrest and mild G1 arrest with LDRI alone, but mild G1 arrest with MTH alone, and mild G2-M, S-phase accumulation with KNK437 alone. The marked G2 arrest caused by LDRI was partially suppressed by the addition of MTH, and was also suppressed by KNK437 treatment. CONCLUSIONS: Exposure of A549 cells to KNK437 caused inhibition of hsp72 and hsp27 expression. The addition of KNK437 increased not only thermosensitivity to MTH, but also radiosensitivity to LDRI. KNK437 also enhanced the MTH-induced radiosensitization under these experimental conditions.

Adaptation, Physiological↗

PubMed2006

Radiosensitization of tumor cells by modulation of ATM kinase.

PURPOSE: To elucidate the relationship between the radiation-induced activation of ataxia telangiectasia mutated (ATM) kinase, G2 arrest and the caffeine-induced radiosensitization. METHOD: RKO cells (human colorectal cancer cells) and ATM kinase over-expressing RKO/ATM cells were used. The cellular radiosensitivity was determined with clonogenic survival assay and the cell cycle progression, including G2 arrest, was studied with flow cytometry. The activity of ATM kinase, check point 2 (Chk2) kinase and cycline B1/cell division cycle 2 (Cdc2) kinase was investigated. The radiosensitivity of RKO xenografts grown in nude mice was studied. RESULTS: RKO/ATM cells were radioresistant as compared with RKO cells. There was a greater increase in ATM kinase activity and G2 arrest in RKO/ATM cells than in RKO cells. Caffeine also sensitized both RKO cells and RKO/ATM cells to radiation. The caffeine treatment suppressed the radiation-induced activation of ATM kinase, suppressed the activation of Chk2 kinase and inhibited the accumulation of cells in G2 phase. The activity of cycline B1/Cdc2 kinase increased earlier but decayed rapidly in the presence of caffeine. Caffeine enhanced radiation-induced growth delay of RKO xenografts. CONCLUSIONS: Caffeine inhibited the radiation-induced activation of ATM kinase, thereby preventing the accumulation of cells in G2 phase. Consequently, radiosensitivity of cells increased in the presence of caffeine both in vitro and in vivo.

Apoptosis↗

PubMed1977

Free-radical formation in gamma-irradiated oriented DNA containing electron-affinic radiosensitizers.

Electron paramagnetic resonance (e.p.r.) was used to study the free radicals induced by gamma-irradiation at 77 K in oriented DNA with incorporated electronaffinic radiosensitizing compounds (4-nitroacetophenone, metronidazole, and Ro-07-0582). The observed e.p.r. spectra were compared with those obtained from pure oriented DNA, which had previously been analysed in detail and found to consist mainly of two components, arising from anion redicals on thymine, and cation radicals on guanine. The major spectral changes caused by the radiosensitizers could be explained as a considerable increase in the formation of cationic free radicals on guanine. There were also indications of the formation of anion radicals on the radiosensitizer molecules. No hydrogen-addition free radicals on thymine were observed when the radiosensitized samples were annealed, in contrast to the pure DNA samples.

Acetophenones↗

PubMed1981

Radiosensitization of microorganisms by radical anions. II. Streptococcus faecalis.

The inactivation of Streptococcus faecalis by radiolytically generated selective inorganic radical anions was investigated. The Br-2 radical, but not (CNS)-2, had a pronounced radiosensitizing action. In gamma-irradiated solutions at pH 7.0, the radiosensitization of a variety of scavenging systems was studied. Among these the D10 for N2/Br- was 0.082 kGy while N2O/CNS- = 0.35 kGy, N2O = 0.25 kGy, N2 = 0.47, and O2 = 0.16 kGy. As shown previously, inactivation in N2O/Br- systems is due mainly to Br2 and HOBr. From the variation of the inactivation with pH by Br-2 and (CNS)-2 it was deduced that tyrosine is crucial for the survival of S. faecalis via inactivation of enzymes with essential tyrosine residues such as aldolase and lipoyl dehydrogenase which are presumably needed to make energy available for DNA repair. Studies with a variety of scavengers also revealed that the t-butanol radical produced some radiosensitization of S. faecalis while the damaging effect of e-aq was much less than OH as shown by the D10 at pH 7.0; N2/t-butanol = 0.32 and N2/ethanol = 0.71. The radiosensitizing action of Br-2 in a natural environment containing sewage sludge was also determined, using the faecal streptococcal group as test organisms.

Anions↗

PubMed1984

Association of the radiosensitizers metronidazole and misonidazole (RO-07-0582) with bovine serum albumin. Effect of urea and ionic strength.

The stability of association of nitroimidazole radiosensitizers (metronidazole and misonidazole) with bovine serum albumin (BSA) was examined in aqueous solutions by 1H n.m.r. spectroscopy in the presence of urea (0-8M) as denaturant, or high salt concentration (NaCl0-5M). A broadening of n.m.r. lines of the two radiosensitizers observed in the presence of BSA disappeared with increasing urea concentration. An especially large narrowing effect was observed for the lines attributed to the methylene group near to the hydroxyl in the side chain of misonidazole. The results suggest a release of both radiosensitizers from their binding sites on unfolding by urea of the polypeptide chain of BSA. The increase of ionic strength I caused a monotonic enhancement of broadening by BSA of the metronidazole lines. For misonidazole, the enhancement of broadening was observed at values of I greater than 1, but at low (less than 1 M) concentrations of NaCl the broadening disappeared. Thus, the results obtained in the systems with salt reflect quantitative changes in hydrophobic and hydrogen-bonded contributions to binding of aliphatic moieties of radiosensitizers to BSA.

Magnetic Resonance Spectroscopy↗

PubMed1986

Radiosensitization by cisplatin of RIF1 tumour cells in vitro.

The ability of cis-diamminedichloroplatinum (II) (c-DDP) to enhance radiation-induced cell killing was tested on oxic RIF1 tumour cells in monolayer culture. Marked radiosensitization of the survivors of a 1 h drug treatment was found with all c-DDP doses tested, with enhancement ratios increasing from 1.2 to 2.2 with increasing drug dose. Isobologram analyses showed that the interactions of c-DDP with X-rays were supra-additive. To test whether part of the enhancement was due to a selection of subpopulations, the diploid and tetraploid RIF1 cells, which normally coexist in culture, were separated by unit gravity velocity sedimentation, and by developing diploid and tetraploid clones. Both methods showed that there was little difference in either drug sensitivity or radiation sensitivity between diploid and tetraploid cells. DNA histograms obtained by flow cytometry showed little or no cycle progression during the 1 h drug treatment. These data indicate that the radiosensitization was not the result of the drug exposure leaving cells in a radiosensitive phase. The observed radiosensitization, therefore, appears to have resulted from a true drug/X-ray interaction.

Cell Cycle↗

PubMed1987

Possible importance of PLD repair in the modulation of BrdUrd and IdUrd-mediated radiosensitization in plateau-phase C3H10T1/2 mouse embryo cells.

C3H10T1/2 mouse embryo cells exhibiting strong contact inhibition of growth at confluency were grown in the presence of 5-bromodeoxyuridine (BrdUrd) or 5-iododeoxyuridine (IdUrd) (0-1.2 microM) with daily refeeding and exposed to gamma-rays (6 Gy) either in the logarithmic or the plateau phase of growth. Sensitization to radiation was observed in both growth states with increasing concentration of BrdUrd or IdUrd but the degree of sensitization achieved was lower for plateau-phase cells. Because the degree of [H3]BrdUrd incorporation was found to be similar in exponentially growing and plateau-phase cells, it is hypothesized that the radiosensitization caused by pyrimidine analogues may be affected by the physiological state of the cells at the time of irradiation. Delayed plating of plateau-phase cells (6 h) caused an increase in survival, indicating repair of potentially lethal damage (PLD). A greater increase in cell survival was observed in cells that had been grown in the presence of BrdUrd and IdUrd and it was found to increase with increasing concentrations. This analogue-concentration dependent PLD repair activity resulted in an almost complete loss of the radiosensitizing effect in delayed plated plateau-phase cells up to a concentration of about 0.6 microM of BrdUrd and IdUrd. Both compounds, but especially BrdUrd, caused a relaxation in the mechanism of contact inhibition and led to higher cell densities in the plateau phase. The results suggest that repair and/or expression of PLD might be involved in the mechanism underlying BrdUrd and IdUrd-mediated radiosensitization and point out the potential importance of PLD repair in the modulation of the radiosensitizing effect of these compounds in their clinical application.

Animals↗

PubMed1987

Further studies on toxic and radiosensitizing properties of ruthenium complexes of 4-nitroimidazoles.

Transition metal complexes containing nitroimidazole ligands have been shown previously to act as radiosensitizers of hypoxic cells in vitro. As part of our study on metal-radiosensitizer complexes, we were encouraged by a ruthenium (Ru) sensitizer, RuCl2(DMSO)2(4(5)-nitroimidazole)2, 1, which showed better radiosensitizing properties and lower toxicity than the free ligand. In this study, we have extended our investigation to include the various other substituted 4-nitroimidazoles as ligands. The new Ru complexes, analogues of 1, were synthesized, identified and characterized and their toxicity and radiosensitizing abilities examined in vitro using Chinese hamster ovary (CHO) cells. Like 1, each of these ruthenium complexes has lower CHO hypoxic toxicity than the free ligands alone at equimolar concentration. These newer complexes gave sensitizing enhancement ratio (SER) values of 1.1 to 1.3 at 1.0 X 10(-4) mol dm-3 compared with 1.6 for 1. Unlike complex 1, the new complexes do not bind to plasmid DNA (assessed by inhibition of restriction endonuclease activity), possibly because the chloride (Cl-) ligand does not dissociate. In addition, the redox potential of the coordinated imidazole ligands is relatively unchanged compared to that of the free ligand. These factors may explain the more favourable properties of 1 compared with those of the new 4-nitroimidazole complexes of Ru.

Animals↗

PubMed1987

Rapid-mixing studies of radiosensitivity with thiol-depleted mammalian cells.

A moderate reduction in the non-protein thiol content of V79 379A Chinese hamster cells, obtained by pretreatment with buthionine sulphoximine (BSO), diethyl maleate (DEM) or N-ethyl maleimide (NEM), increase both the absolute radiosensitivity of the cells in hypoxia and the radiosensitizing effect of adding oxygen 7 ms after irradiation. Combined pretreatment of cells with BSO and NEM removes most of the non-protein thiol and some of the protein thiol; such treatment further increases the radiosensitivity of hypoxic cells but there is no further effect of adding oxygen 7 ms after irradiation. Addition of 2-mercaptoethanol to cells 7 ms after irradiation gives protection factors that increase with increasing severity of thiol depletion. Substantial radioprotection can still be observed when 2-mercaptoethanol is added 70 ms after irradiation of cells pretreated with BSO and NEM; there is no effect of adding 2-mercaptoethanol to such cells 50s after irradiation. These observations support the repair-fixation model of radiation damage and suggest that, in addition to the established role of non-protein thiol in chemical repair of radiation damage, other endogenous reducing agents such as protein thiol may be important in determining cellular radiosensitivity. A relatively long-lived thiol-modifiable component of radiation damage has been observed within hypoxic thiol-depleted cells.

Animals↗

PubMed1988

Radiosensitive human tumour cell lines may not be recovery deficient.

Split-dose studies have been performed on four human tumour cell lines of widely differing radiosensitivity in order to characterize the relationship between cellular recovery and radiation dose. Previous studies using the split-dose experiment have usually measured recovery at a single dose level and assumed an underlying multi-target model of radiation effect. This predicts that the recovery ratio should reach a plateau when the dose used per fraction is beyond the shoulder of the acute survival curve. In contrast, the linear-quadratic model predicts that the recovery ratio will increase steeply as a function of dose and will never reach a plateau. Our results show that recovery increases with increasing dose and therefore no single value of the recovery ratio can be used for comparative purposes. Using these data, we have derived a value for the beta-component of the linear-quadratic model that is independent of alpha. In addition we propose that the beta-parameter derived in this way provides the most satisfactory basis for intercomparison of cellular recovery between cell lines of differing radiosensitivity. Cellular recovery at any given dose was greatest in the most radiosensitive cell line, suggesting that increased radiosensitivity does not result from decreased recovery capacity. The results suggest that cells with steep acute radiation survival curves and which show little split-dose recovery may not be recovery deficient. Consequently, using such cells in attempts to correlate recovery with the underlying molecular processes of radiation damage repair could lead to misleading results.

Cell Line↗

PubMed1989

Radiosensitization of E. coli B/r by arylhydrazonopropanedinitriles.

Several arylhydrazonopropanedinitriles and an arylhydrazonopropane-diethyl ester (derivatives of well-known uncouplers of oxidative phosphorylation) have been studied with respect to their ability to radiosensitize E. coli B/r under oxic and hypoxic conditions. Of the compounds studied, 2-carboxyphenylhydrazono-propanedinitrile and 2-carboxyphenylhydrazonopropanediethylester were found to be the most efficient radiosensitizers under hypoxia, whilst the former compound was also found to provide radiosensitization under oxic conditions. Increased radiosensitization by 4-carboxyphenylhydrazonopropanedinitrile was observed on decreasing the pH of the irradiation incubation medium. The results are discussed with respect to the physicochemical properties of these compounds and their reactivity with thiols, for which data are presented.

Acetylcysteine↗

PubMed1989

The relationship between potentially lethal damage repair and intrinsic radiosensitivity of human cells.

The intrinsic radiosensitivity of exponentially growing cells (exp) was compared to that of immediately plated plateau phase cells (ip) using published data on 60 human cell lines (27 fibroblast lines and 33 tumour cell lines). The values for alpha, D and S2 are not significantly different for the two groups; beta is significantly higher in ip cells. This produces a smaller alpha/beta ratio in ip cells than in exp cells. The influence of potentially lethal damage (PLD) repair was assessed by comparing the radiosensitivities of ip cells and plateau phase cells with delayed plating (dp). The published data for 81 human cell lines (48 fibroblasts and 33 tumour lines) were used. PLD repair was found to lead to a decrease in alpha and an increase in D and S2, whereas neither beta nor the alpha/beta ratio changed significantly. The relationship between PLD repair and intrinsic radiosensitivity was assessed by repair capacity and the repair ratio. The fitted relationship is a bell-shaped curve with a maximum at 2.2 Gy for repair capacity. The fitted curve predicts that repair capacity is zero at a D up of 0.28 Gy and at 4 Gy. Thus, PLD repair is a reasonable reflection of intrinsic radiosensitivity up to 2.2 Gy. Above 2.2 Gy, the relationship is reversed: the greater the radioresistance, the lower the PLD repair.

Cell Cycle↗

PubMed1989

Radiosensitivity of human head and neck squamous cell carcinomas in primary culture and its potential as a predictive assay of tumor radiocurability.

The intrinsic radiosensitivity of human tumor cell cultures correlates with the clinical radiosensitivity of several different tumor histologies, as evidenced by analyses of low dose parameters of radiation survival curves generated from a large number of cell lines. Such radiosensitivity has therefore served as a basis of attempts to develop predictive assays of tumor radiocurability. In this study, the tumors from 72 patients with head and neck squamous carcinoma have been grown in an adhesive tumor-cell assay system and radiosensitivity (S2: survival at 2.0 Gy) values have been measured. The characteristics of these cultures, such as growth rate, clonogenicity and growth enhancement by epidermal growth factor, do not correlate with S2. The average S2 value of the 72 cultures is 0.33, which is lower than for cultures derived from melanomas and lung adenocarcinomas. Twenty-six patients followed up for at least 15 months have been evaluated for local tumor control. The average S2 value of the seven patients with recurrences in this group is slightly higher (0.43) than that from the other patients (0.30). There is considerable overlap of S2 values in the two groups, and more patients must be evaluated before the groups can be compared statistically.

Carcinoma, Squamous Cell↗

PubMed1989

Radiobiology and clinical application of halogenated pyrimidine radiosensitizers.

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.

Bromodeoxyuridine↗

PubMed1989

Manipulation of the radiosensitivity of pig epidermis by changing the concentration of oxygen and halothane in the anaesthetic gas mixture.

A gas mixture of halothane, oxygen and nitrous oxide has been used to anesthetize pigs for irradiation. The effects of various concentrations of halothane and oxygen on the radiosensitivity of the epidermis were examined after irradiation with single doses of beta-rays from strontium-90 plaques. The incidence of moist desquamation was used as an endpoint, and experiments were compared on the basis of the dose associated with a 50 per cent incidence of moist desquamation (ED50 +/- SE). For pigs inspiring an anaesthetic gas mixture of 2 per cent halothane, approximately 70 per cent oxygen and approximately 30 per cent nitrous oxide the ED50 for moist desquamation was 27.32 +/- 0.52 Gy. A similar ED50 value of 27.39 +/- 1.20 Gy was obtained when 4 per cent halothane was used in place of 2 per cent. When the pigs were breathing air (approximately 21 per cent oxygen) in place of oxygen and nitrous oxide the ED50 values were increased significantly to 31.25 +/- 0.94 Gy and 33.72 +/- 1.08 Gy for 2, and 4 per cent halothane, respectively. This change in the radiosensitivity of the epidermis was represented by dose modification factors of approximately 1.13 and approximately 1.23 for 2 and 4 per cent halothane, respectively. Irradiation with a high oxygen concentration in the inspired gas mixture did not result in any significant variation of the dose required to produce moist desquamation in 50 per cent of the fields irradiated for dorsal, lateral and ventral positioned skin fields on the flank. However, pigs breathing air and halothane during irradiation showed marked differences in the radiosensitivity of the various sites on the flank, with ED50 values for moist desquamation of approximately 37 Gy and 26-30 Gy for dorsal and ventral positioned fields, respectively. This marked difference in radiosensitivity suggests variations in the physiological compensation over the flank when pigs are breathing oxygen at low concentrations under anaesthesia.

Anesthesia, Inhalation↗

PubMed1990

Radiosensitivity throughout the cell cycle and repair of potentially lethal damage and DNA double-strand breaks in an X-ray-sensitive CHO mutant.

The response to ionizing radiation of synchronized and plateau-phase populations of xrs-5 cells was studied at the DNA and cellular level. Induction and repair of DNA double-strand breaks (dsb) were measured by the non-unwinding filter elution technique. Biphasic survival curves were obtained throughout the cell cycle as well as in the plateau phase, suggesting the presence in the cultures of a radiation-sensitive and a radiation-resistant subpopulation. Delayed plating of plateau-phase xrs-5 cells did not significantly modify cell survival indicating a deficiency in the repair of potentially lethal damage (PLD). Post-irradiation treatment with araA further indicated a deficiency in the repair of a form of PLD sensitive to this drug in the radiation-sensitive subpopulation. The radiosensitivity of synchronized populations decreased as cells progressed through S. Cells in late S were found to be most resistant to radiation, whereas cells irradiated in G2 + M had a sensitivity similar to that of cells irradiated in G1. The decrease in radiosensitivity in S was tentatively attributed to an increase in the proportion of radioresistant cells in the cell population. Preliminary analysis of the results obtained, assuming the presence of two subpopulations showing an exponential response as a function of dose, indicated no change in the D0 values of the radiation-sensitive and the radiation-resistant component throughout the cell cycle. The D0 value of the radiation-resistant component was similar to the D0 of repair-proficient CHO cells. At no stage in the cell cycle were shoulder-type survival curves observed. Transient expression of the xrs-5 repair gene may underlie the observed variation of radiosensitivity throughout the cell cycle. This gene expression could occur either at random, in a subpopulation of cells independent of cell cycle phase, or in a specific manner related to gene replication and the hemimethylated state transiently found immediately thereafter. It is proposed that the resistant tail observed in the survival curves throughout the cell cycle is due to the former phenomenon, and the decreased radiosensitivity in late S to the latter. xrs-5 cells were found to be deficient in dsb repair in the plateau phase of growth, as well as in G1 and mid-S phase. The latter observation indicates that the reduction in radiation sensitivity in S is not associated with a modulation in the ability of cells to repair dsb.

Animals↗