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PubMed1981

Protein composition of cells, nuclei and chromatin from some radiosensitive and radioresistant mouse tissues.

The radioresistant tissues, heart, liver, lung and kidney, contain 2 to 15 times more protein per cell, nucleus and chromatin compared with the radiosensitive tissues, spleen and thymus. As determined by polyacrylamide gel electrophoresis, in the nuclear fraction and chromatin of radiosensitive tissues there is a deficit of high molecular weight (Mw greater than 20 000) non-histone proteins. It is suggested that the radiosensitivity of lymphoid cells, which die of interphase death a few hours after exposure to small doses of radiation, is closely correlated with this deficit in non-histone proteins.

Animals↗

PubMed1982

A mathematical model resolving normal human blood lymphocyte population x-ray survival curves into six components: radiosensitivity, death rate and size of two responding subpopulations.

The analysis was based on observations of survival decrease as a function of dose (range 0-5 Gy (= 500 rad) and time after irradiation in vitro. Since lymphocyte survival is also sensitive to culture conditions the effects of radiation were examined daily up to 3 days only, while survival of control cells remained ca. 90 per cent. The time-dependent changes were resolved as the death rates (first-order governed) of lethally-hit cells (apparent survivors), so rendering these distinguishable from the morphologically identical, true (ultimate) survivors. For 12 blood donors the estimated dose permitting 37 per cent ultimate survival (D37 value) averaged 0.72 +/- 0.18 (SD) Gy for the more radiosensitive lymphocyte fraction and 2.50 +/- 0.67 Gy for the less radiosensitive, each fraction proving homogeneously radiosensitive and the latter identifying substantially in kind with T-type (E-rosetting lymphocytes). The half-life of lethally-hit members of either fraction varied widely among the donors (ranges, 25-104 hours and 11-40 hours, respectively). Survival curves reconstructed by summating the numerical estimates of the six parameters according to the theoretical model closely matched those observed experimentally (range in multiple correlation coefficient, 0.9709-0.9994 for all donors). This signified the absence of any additional, totally radioresistant cell fraction.

Adult↗

PubMed1982

Supercoiled DNA repair in thymocyte fractions differing in radiosensitivity.

Mouse thymocyte fractions were isolated on the basis of buoyant density in a step-gradient of human serum albumin. These fractions were characterized by cell size, radiosensitivity and hydrocortisone sensitivity, and by labelled precursor incorporation into DNA, RNA and proteins. The relative sedimentation of nucleoids in sucrose gradient was also determined. Large and more radioresistant thymocytes were characterized by an increased rate of DNA repair compared with the fraction of radiosensitive small lymphocytes. Nucleoids prepared from the small thymocyte fraction had greater relative sedimentation rates than those derived from large cells. The response of relative sedimentation of nucleoids from large and small thymocyte fractions to ethidium bromide concentration does not permit a conclusion on different superhelix density for DNA in cells of these fractions. At the same time the estimate of the supercoiled domain size for nucleoids of large and small thymocyte fractions showed that in the more radiosensitive small cells domains of greater size were predominant.

Animals↗

PubMed1984

Thiol reactive nitroimidazoles: radiosensitization studies in vitro and in vivo.

Using Chinese hamster V79 cells in vitro a study has been made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E17 (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, C1.6/C1.6, by which a compound is more efficient has been calculated. The second-order rate constants, k2, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol were determined. Within each class of nitroimidazole there is a trend for k2 to increase with increasing redox potential. However, there is no clear trend between k2 and C1.6/C1.6. The concentration required to cause a 50 per cent depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-transferase to catalyse reaction with thiols. These observations suggested that the relative thiol reactivity measured under chemically controlled conditions does not necessarily indicate thiol reactivity intracellularly. Studies using the MT tumour in mice showed that the high levels of radiosensitization seen in vitro could not be duplicated in vivo. This was attributed to thiol reactivity, resulting in low metabolic stability and rapid depletion of sensitizer in vivo.

Animals↗

PubMed1985

The effect of extracellular pH on radiosensitization by misonidazole and acidic or basic analogues.

The effect of extracellular pH (pHe) on the radiosensitization of hypoxic Chinese hamster V79 cells in vitro by the 2-nitroimidazole, misonidazole, and analogues substituted with basic or acid functions has been studied. Misonidazole (1 mmol dm-3) gave an enhancement ratio (e.r.) of 1.6 which remained unchanged over the pHe range of 3.8-9.5. Control hypoxic survival curves in the absence of sensitizer also remained essentially unchanged over this pHe range. These results contrast with those seen for 0.1 mmol dm-3 Ro 03-8799 (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propanol), a base with pKa = 8.9): the ER increased from 1.4 to 2.1 as pHe increased from 5.6 to 8.4. However, with the weaker bases, Ro 03-8800 and nimorazole (morpholino derivatives with pKa = 6.3 and 5.2 respectively) the e.r. remained constant over a wide pHe range. Nitroimidazoles substituted with acidic functions gave decreasing sensitization with increasing pHe. For azomycin (pKa = 7.2) at 1 mmol dm-3 the e.r. decreased from 1.9 at pHe 4 to 1.0 at pHe 9. The effect of the proton conductor carbonyl cyanide-3-chlorophenylhydrazone (CCCP, 10 mumol dm-3) on radiosensitization by Ro 03-8799 (0.1 mmol dm-3) and misonidazole (1.0 mmol dm-3) was also studied. At pHe 6.67 the e.r. for Ro 03-8799 was increased from 1.36 to 1.76 by the presence of CCCP, whereas at pHe 7.33 the e.r. was unchanged. In contrast the e.r. for misonidazole was unchanged at pHe 6.65 and 7.33. These results are consistent with pH differentials across the cell membrane creating intracellular:extracellular concentrations gradients for radiosensitizers with acidic or basic functions.

Animals↗

PubMed1985

Effect of heat on radiosensitivity at different developmental stages of embryos of the fish Oryzias latipes.

Embryos of the fish, Oryzias latipes, at various developmental stages were heated before or after gamma-irradiation. The lethal effects of heat and radiation treatments were determined by the hatchability of the irradiated embryos. The radiosensitivity suddenly decreased at 3-days after fertilization. Heat (41 degrees C), either preceding or following irradiation, decreased the shoulder region (Dq) of the dose-response curves of the embryos irradiated at the 1-3 day stages, and increased the slope (D0) only at the 3 day stage. The magnitude of enhancement of radiosensitivity by pre- and post-heating was found to depend on the time and temperature of the heat as well as the developmental stage of the embryos; in 1- and 2-day embryos the effectiveness of post-irradiation heating was larger than that of pre-irradiation heating whereas in 3-day embryos there was no difference between the effectiveness of pre- and post-treatment. The sequence of heat (41 degrees C) and radiation treatment, and the time interval between the two treatments, also influenced the effectiveness of heat on radiosensitivity, depending upon the developmental stage; recovery from heat effects was not observed within a time interval of up to 3 h before radiation exposure for either 1- or 3-day embryos, whereas recovery from the radiation lesion occurred, for only 1-day embryos, within 1 h of subsequent heat exposure.

Age Factors↗

PubMed1985

The intrinsic radiosensitivity of lymphocytes in chronic lymphocytic leukaemia, quantitatively determined independently of cell death rate factors.

Survival curve shape for lymphocytes X-irradiated in vitro is governed by death rate as well as intrinsic radiosensitivity. We have resolved into these two components the survival curves obtained for CLL lymphocytes by use of a simple mathematical model. A multiple correlation coefficient comparing the predicted with the experimental survival curves was close to unity (0.954-0.999). For 14/18 patients with unequivocal B-cell CLL, the leukaemic (colchicine ultrasensitive) cells behaved as a homogeneous population (D37 0.32-1.28 Gy). This is similar to the more radiosensitive class of lymphocytes of normal blood (believed to include the B cells) and is some 4-fold less than the more radioresistant class (comprising most of the T cells). The lethally hit cells were homogeneous in death rate, which followed first order kinetics. The half-life (range 9-87 h) was, on average, some 50 per cent shorter than the more radiosensitive normal lymphocytes. The remaining four patients constituted a miscellaneous group. From one of these, it can be seen that an excessively slow death rate can give the misleading impression of radioresistance. It is hypothesized that the benefit afforded certain CLL patients treated with low-dose total body irradiation (TBI) or splenic irradiation (SI) may reside, partly, in the sparing of T lymphocytes of the helper type and in accompanying selective elimination (or functional inactivation) of those of the suppressor type.

Cell Survival↗

PubMed1986

Differential radiosensitization of human tumour cells by 3-aminobenzamide and benzamide: inhibitors of poly(ADP-ribosylation).

The effect of 3-aminobenzamide (3AB) and benzamide (BZ) (inhibitors of poly(ADP-ribose) synthetase) on radiosensitivity was investigated in normal human fibroblasts and three human cell lines established from tumours with varying degrees of clinical radiocurability. The human tumour cell lines selected were: Ewing's sarcoma, a bone tumour usually considered radiocurable with moderate radiation doses; lung adenocarcinoma, a tumour considered radiocurable with high doses of radiotherapy; and osteosarcoma, a very resistant tumour which is rarely controlled by standard doses of radiotherapy. Poly(ADP-ribose) synthetase inhibitors were added to cultures 2 h prior to irradiation and removed 24 h after. Inhibitors were used at doses producing little or no toxicity in cells. In the presence of these inhibitors, a differential radiosensitization was observed. Ewing's sarcoma cells and normal human fibroblasts were sensitized to an equal extent by either 8 mM 3AB or 4 mM BZ. However, no sensitization was observed at these concentrations in the lung adenocarcinoma cells or osteosarcoma cells. The degree of radiosensitization in vitro by 3AB and BZ correlates well with the clinical radiocurability of these tumours in vivo.

Benzamides↗

PubMed1987

Binding mode of 2-amino-5-nitrothiazole (ANT) in platinum complexes, trans-[PtCl2(ANT)2], affects DNA binding, toxicity and radiosensitizing ability.

The radiosensitizer 2-amino-5-nitrothiazole (ANT) can react with platinum to form many products because of the availability of two potential nitrogen donors as ligands for metals. Two of these complexes, both with two ANT molecules in the trans configuration, differ because of their linkages. In the first, Pt is bound to ANT via the amine group (A) and in the second via the thiazole ring nitrogen (R). Isomer R is a better radiosensitizer than A in hypoxic Chinese hamster ovary cells, giving enhancement ratios of 1.6 versus 1.15 with 100 mumol dm-3 complex. The ring-bound isomer also exhibits higher toxicity than the amine bound in air and under conditions of hypoxia. Sensitization by isomer R is much higher under conditions of hypoxia than in air. In an assay to assess DNA binding, isomer R inhibited restriction enzyme cleavage of DNA but isomer A did not (up to 6 h at 300 mumol dm-3). It appears from this study on two very similar complexes that the complex which exhibits stronger binding may be targetting the radiosensitizer to the DNA, resulting in greatly improved sensitization.

Animals↗

PubMed1989

Trypsinization and the radiosensitivity of mitotic and log phase Chinese hamster V79 cells exposed to 250 kVp X-rays.

We studied the influence of trypsin-induced morphological changes on the radiosensitivity of cells plated at either low (4-600/cm2) or high (2 x 10(4)/cm2) density and grown overnight before treatments. Trypsin treatment induced contraction and rounding of spread cells. The radiosensitivity of cells trypsinized and plated either: (1) immediately before [(a) D0 = 1.7 Gy for cells at low-, and (b) 1.5 Gy at high-density] or (2) immediately after (D0 = 1.6 Gy, high-density cells) irradiation was higher than that of (3) cells at high density, irradiated and delayed plated [cells remained spread until the completion of potentially lethal damage repair (PLDR) and trypsinization, D0 = 2.2 Gy], and (4) cells at low density which were neither delayed plated nor trypsinized (i.e. remained spread) after irradiation (Do = 2.4 Gy). These data show that PLDR is reduced in trypsin-treated cells of both high (compare 1b and 2 with 3) and low (compare 1a with 4) density cultures; the latter comparison provides a direct measure of the trypsin effect. Since the comparison between conditions 1 and 2 vs. 3 and 4 is of round vs. spread cells, PLDR appears to be influenced by the cell's morphological state. Kinetic studies showed that when cells were incubated in growth medium to recover from trypsin-induced effects before irradiation, the radiation sensitivity of spread cells (plated in situ), but not of those remaining rounded (in suspension until plating and irradiation), decreased and became equal to that of delayed plated high-density cells. Neither irradiated cells treated with hypertonic saline, nor mitotic cells, showed the trypsin effect. From these results we suggest that: (1) trypsin-induced cell contraction affects the ability of cells to repair radiation damage, (2) spread cells are better able to repair PLD than rounded cells, (3) immediate plating survival of cells in high-density cultures may not represent their intrinsic radiosensitivity and (4) cell-to-cell contact is not necessary for log phase cells to repair PLD.

Animals↗

PubMed1989

Radiosensitization by quaternary salts of 5-nitroimidazole derivatives.

The radiosensitizing effects of five newly synthesized quaternary salts of 5-nitroimidazole derivatives on the survival of TC-SV40 mammalian cells have been measured. A toxicity study was carried out in order to determine the concentrations to be used in the radiosensitizing experiments. The oxygen enhancement ratio (OER) for TC-SV40 cells was 2.74. None of the five 5-nitroimidazole derivatives showed radiosensitizing activity in aerobic conditions, while in hypoxia their dose-modifying factors (DMF) at the concentration of 0.2 mmol dm-3 range from 1.52 to 1.03 in this order: unsubstituted pyridinium greater than carbamoyl pyridinium greater than trimethyl pyridinium greater than t-butyl pyridinium greater than imidazolium. This latter product at the concentration of 2 mmol dm-3 has a DMF of 1.64. As comparison, metronidazole was also tested on this cell line and its DMF at 0.2 mmol dm-3 was 1.35. The response-concentration dependences for the unsubstituted pyridinium 5-nitroimidazole derivative and for metronidazole (comparing charged and uncharged structures) showed the flattening response-concentration curve of quaternary compounds. The electron affinity was evaluated through the CNDO/S theoretical method, and an exponential relationship between these values and the DMFs of the pyridinium derivatives was demonstrated.

Animals↗

PubMed1990

Radiosensitization by metal complexes of 4(5)-nitroimidazole.

Four closely-related cis-platinum (Pt) complexes of 4(5)-nitroimidazole have been examined with respect to properties of radiobiological interest, to test the hypothesis that targeting a nitroimidazole (NO2Im) to DNA could enhance its radiosensitizing ability: I [PtCl2(5-NO2Im)2]; II [PtCl2(4-NO2Im)2]; III [PtCl2(NH3)(5-NO2Im)]; IV [PtCl2(NH3)(4-NO2Im)]. The reduction potential was affected to the same extent on metal binding in all of the complexes (delta E1/2 = +200 mV, cf. ligand measured polographically). Higher sensitization by 5-NO2 complexes I, III (cf. II, IV) was found. Only the mono complexes III and IV bind to DNA (in an assay using inhibition of restriction endonuclease activity); these radiosensitize as well as, or better than, free ligand in hypoxic CHO cells, and better than the bis complexes (I and II). The toxicity of the mono complexes is higher than ligand, and parallels the binding (III, IV, mono bis analogues). The complexes are compared with 4-nitroimidazole complexes of ruthenium, with respect to toxicity, binding and radiosensitization.

Animals↗

PubMed1990

Enhancement of radiosensitivity of cultured mammalian cells by neocarzinostatin. I. Inhibition of the repair of sublethal damage.

The enhancement of radiosensitivity by neocarzinostatin (NCS), an antitumour drug, was studied using three strains of cultured mammalian cells with different repair capabilities for sublethal damage. NCS enhanced the radiosensitivity of the cells when applied both during and after X-irradiation under aerobic conditions. The enhancement ratios of NCS during X-irradiation were 1.25, 1.27 and 1.38 for mouse lymphoma L5178Y, Chinese hamster V79 and mouse mammary tumour FM 3A cells, respectively. The corresponding ratios after X-irradiation were 1.18, 1.27 and 1.38, respectively. These ratios were proportional to the repair capabilities of the cells for sublethal damage. NCS completely inhibited the repair of sublethal damage regardless of the repair capabilities of the cells for sublethal damage. NCS was equally effective for hypoxic cells. These results suggested that NCS enhanced the radiosensitivity of the cells probably by interacting with the residual damage after X-irradiation, thereby converting the sublethal damage or potentially lethal damage into lethal damage.

Animals↗

PubMed1991

Analysis by pulsed-field gel electrophoresis of DNA double-strand breakage and repair in Deinococcus radiodurans and a radiosensitive mutant.

Double-strand break (dsb) induction and rejoining after ionizing radiation was analysed in Deinococcus radiodurans and a radiosensitive mutant by pulsed-field gel electrophoresis. Following 2 kGy, migration of genomic DNA (not restriction cleaved) from the plug into the gel was extensive, but was not observed after 90 min postirradiation recovery. By this time D. radiodurans chromosomes were intact, as demonstrated by restoration of the Not I restriction cleavage pattern of 11 bands, which we found to be the characteristic pattern in unirradiated cells. Following the higher exposure of 4 kGy, dsb rejoining took approximately 180 min, twice as long as required following the 2 kGy exposure. Restoration of dsb in the radiosensitive mutant strain 112, which appears to be defective in recombination, was markedly retarded at both 2 and 4 kGy. The Not I restriction fragments of wild-type D. radiodurans and the radiosensitive mutant were identical, totaling 3.58 Mbp, equivalent to 2.36 x 10(9) daltons per chromosome.

DNA↗

PubMed1993

Correlation between thermal radiosensitization and heat-induced loss of DNA polymerase beta activity in CHO cells.

The increase in radiosensitivity caused by various kinds of single and combined heat treatments was studied in CHO cells and related to the heat-induced loss of the DNA polymerase beta activity. Thermal radiosensitization was quantified by the thermal enhancement ratio TER10% determined on the 10% survival level and by the parameters alpha and beta obtained from fitting cellular survival data to the equation -ln(S/S0) = alpha D + beta D2. The values for TER10% and the alpha-term showed only a poor correlation with the inverse of polymerase beta activity; the data for single heating at temperatures exceeding 41.5 degrees C and the data for thermotolerant cells fell on the same straight line, whereas for single heating at T < or = 41.5 degrees C and for cells exposed to a high-to-low temperature sequence (step-down heating) the increase in TER10% and alpha was much steeper than found for the other heat treatments. By contrast, a linear relationship was shown to exist between the beta-term of cellular radiosensitivity and the loss of polymerase beta activity as expressed by the reciprocal value of the enzyme activity. This relationship was the same for all kinds of heat treatments applied, suggesting that for CHO cells the increase in the beta-term observed after combined treatment with heat and radiation might be causally related to the heat-induced loss of polymerase beta activity.

Animals↗

PubMed1993

Use of low-dose rate irradiation to measure the intrinsic radiosensitivity of human T-lymphocytes.

A comparison has been made of high (1.55 Gy min-1) and low dose-rate (0.0098 Gy min-1) irradiation in determining the intrinsic radiosensitivity of peripheral blood lymphocytes from normal individuals. Samples from 19 people were assessed using a limiting dilution assay and used to investigate the variability associated with evaluation of lymphocyte radiosensitivity after both high and low dose-rate irradiation. Repeat experiments on a single sample from one donor stored over a period of 6 months have been used to compare assay variability using the different dose-rates. Multiple samples taken from a single person over a period of 5 months were assayed at low dose-rate to assess intraindividual variation in measured in vitro radiosensitivity. At high dose-rate significant interexperimental variation in the measured parameters was demonstrated and, after allowing for this variability, no significant interindividual differences were found. At low dose-rate, sparing of cell kill was seen for all lymphocytes and led to an increase in the spread of data between individuals such that interindividual differences reached statistical significance for surviving fraction at 4 Gy, alpha (linear fit) and D with p < 0.004 for all parameters.

Cell Survival↗

PubMed1993

Use of an internal standard in comparative measurements of the intrinsic radiosensitivities of human T-lymphocytes.

A study has been made of the intrinsic radiosensitivity of peripheral blood lymphocytes from normal individuals. Cell survival following in vitro high (1.55 Gy min-1) and low (0.0098 Gy min-1) dose-rate irradiation was obtained for single lymphocyte samples from three individuals in six experiments. Despite wide interexperimental variability the ranking of intrinsic radiosensitivity for these individuals was reproducible. Further studies were carried out using low dose-rate irradiation only, on: (1) single lymphocyte samples from 18 people; (2) 14 samples taken on different occasions from one of these donors over a period of 5 months; and (3) a large store of lymphocytes from another individual. The latter was assayed in every experiment and served as an internal standard to which results could be normalized. In comparison with uncorrected values, the normalized results for the 14 samples from the single individual showed a reduction in the spread of data while those for the 18 different donors were unchanged. An analysis of variance was carried out on a larger data set of 38 measurements which included repeat assays on several of the samples (two samples from the multiply-sampled individual and five samples from other donors were assayed twice). In comparison with the uncorrected values, the normalized results showed a reduction in experimental variability such that the coefficient of variation (CV) for surviving fraction at 4 Gy for the multiple samples from a single individual decreased from 41 to 19%. In contrast, there was little change in the variation between 18 individuals with CVs of 56 and 62%, respectively, for uncorrected and normalized results. These data suggest that the use of an internal standard for the determination of the intrinsic radiosensitivity of individuals using peripheral blood lymphocytes should aid the development and evaluation of predictive tests for the radiotherapy of cancer.

Cell Survival↗

PubMed1993

Radiosensitization and radioprotection of E. coli by alcohols.

The survival of E. coli K12 strain AB1157 and the isogenic repair-deficient mutant E. coli AB2480 (recA13, uvrA6) was measured after gamma-irradiation in the presence of various alcohols as well as after incubation and subsequent removal of the alcohols before irradiation. Irradiation in the presence of alcohols leads to the already known protection effect, which has been attributed to OH radical scavenging. However, it was not possible to explain the protection solely in terms of the reactivity of the OH radical with the various alcohols, because addition of some of the alcohols did not yield the expected survival values. It was found that incubation with and subsequent removal of various alcohols before irradiation led to radiosensitization. The degree of radiosensitization increases with the hydrophobicity of the alcohol. In the case of glycerol no radiosensitization was observed. We can conclude that alcohols protect predominantly by OH radical scavenging. The comparatively small protection of cell survival by the more hydrophobic alcohols can be attributed to the sensitizing effect of these alcohols.

1-Propanol↗