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PubMed1990

Radiosensitization by misonidazole, pimonidazole and azomycin and intracellular uptake in human tumour cell lines.

The radiosensitization of two human tumour in vitro cell lines, HT-1080 and LoVo, has been compared with that of the Chinese hamster cell line V79-379A. Although the two human tumour cell lines were more radiosensitive than the V79 cell line sensitizer, enhancement ratios for misonidazole, pimonidazole and azomycin were similar (relative to extracellular concentration) for all three cell lines. Average intracellular concentrations of radiosensitizer were measured by high-performance liquid chromatography. In all three cell lines the uptake of misonidazole and azomycin was extremely rapid whereas that of pimonidazole was initially much slower before reaching a plateau. The ratios of intracellular concentration of radiosensitizer to extracellular concentration (Ci to Ce) for misonidazole were 0.8 (HT-1080) and 0.7 (LoVo and V79); for azomycin 0.9 (HT-1080 and LoVo) and 0.8 (V79). In contrast Ci/Ce for pimonidazole varied with cell line, the values being 1.8 (LoVo), 2.6 (HT-1080) and 3.3 (V79). Intracellular amounts of non-protein sulphydryl (NPSH) varied between cell lines by about a factor of three. However, when the average cell volume was taken into consideration the concentrations of NPSH were very similar, being 4.2 (HT-1080), 5.6 (LoVo) and 5.7 (V79) mmol dm-3. NPSH levels expressed as nmol per mg protein were also similar.

Animals↗

PubMed1991

Influence of circadian rhythms on radiosensitivity: single and fractionated dose studies in mouse skin.

In rodent skin significant increases in labelling and mitotic indices have been reported during the period of maximum nocturnal activity. It has been suggested that sparing of radiation damage in fast-proliferating normal tissues could be achieved if treatments were given at the time of day when the maximum number of normal cells were most radioresistant. If changes in radiosensitivity do occur in tissues with circadian fluctuations in the cell kinetic parameters, then the magnitude of these changes should be dependent on the size of dose per fraction. Because of the implications for clinical radiotherapy, especially in regimes where multiple fractions per day are given (MFD), possible diurnal variations in radiosensitivity were investigated using single dose and fractionated X-ray regimens (5F/5 days, 8F/8 days), in rodent skin. Treatments were delivered at 1, 3, 5 a.m. (time of highest DNA synthetic activity in mouse epidermis), 6 and 7 a.m. (highest mitotic activity) and at 5 p.m. (minimum labelling and mitotic indices). To investigate a large range of doses per fraction, fractionated X-rays were given alone or followed by neutron top-up doses. Using a range of doses per fraction of 30 Gy down to 1 Gy, we did not detect any change in radiosensitivity with any of the schedules. Our results suggest that a decrease in normal tissue tolerance is unlikely to be observed in patients even if irradiated at a time of day at which a maximum increase in radiosensitivity might be predicted on the basis of a high mitotic index.

Animals↗

PubMed1991

Comparative human cellular radiosensitivity: III. Gamma-radiation survival of cultured skin fibroblasts and resting T-lymphocytes from the peripheral blood of the same individual.

Skin and blood samples were obtained from 34 donors, for whom there was no indication of abnormal radiosensitivity. From these, in 33 cases both fibroblast and T-lymphocyte cultures were obtained and in 26 cases at least three fibroblast and at least two G0 (resting) T-lymphocyte survival assays were possible. Within this set of results, differences in radiosensitivity between donors were significant for fibroblasts but not T-lymphocytes, although the range of radiosensitivity was similar for the two cell types (D 0.90-1.68 Gy for fibroblasts; 1.26-2.15 Gy for T-lymphocytes). Furthermore, there was little evidence for a correlation in radiosensitivity between the two cell types. These results suggest limitations in the predictive value of conventional measurement of cell survival.

Cell Survival↗

PubMed1992

A potential pitfall in the use of electroporation: cellular radiosensitization by pulsed high-voltage electric fields.

Chinese hamster ovary cells have been exposed to high-voltage electric fields causing electroporation (EP) and the interaction between EP and radiation-induced cell lethality investigated. There was a voltage-dependent decrease in plating efficiency, assessed immediately following EP, and cell viability, assessed at 24 h. A linear decrease was seen for both. These decreases were accompanied by a voltage-dependent increase in cell volume, assessed immediately following EP. A good correlation between increases in cell volume and decreases in plating efficiency was seen (r = -0.91). The application of electric fields immediately prior to, or following, irradiation led to a radiosensitization of the cells. This radiosensitization still occurred when a 6 h interval was left between radiation and EP but was lost when cells were irradiated 24 h prior to EP. When cells were irradiated following EP, the radiosensitization was lost with a 1 h interval between the two treatments. These results suggest that, when studying the combined cellular effects of EP of macromolecules and radiation, care should be taken that sufficient time has elapsed between the two modalities to prevent the radiosensitization of cells.

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

Relationship between intracellular concentration and radiosensitizing effect of pimonidazole and etanidazole on two human melanoma cell lines.

A study on the uptake and radiosensitizing properties of pimonidazole (PIMO) and etanidazole (ETA) was made in vitro with two melanoma cell lines: Na11+ and Na11-. The amelanotic Na11- was derived from the pigmented Na11+ cell line and was characterized by the complete absence of pigmentation in vitro. Plateau-phase cells were heavily pigmented for the Na11+ line whereas exponential cells showed a lower melanin content. Radiosensitivity was studied using an in vitro colony assay; intracellular drug concentration was determined by HPLC. For both cell lines the uptake of PIMO was always higher than the uptake of ETA, and slightly higher in hypoxia than in air. The uptake of PIMO was exceptionally high in plateau-phase cells of the pigmented Na11+ cell line. The radiosensitizing effect of ETA did not differ greatly as a function of the cell kinetics in both cell lines, whereas the radiosensitizing effect of PIMO was cell line-dependent. Sensitization of exponential cells by PIMO was similar in both cell lines but significantly less in plateau-phase cells, with the heavily pigmented Na11+ cell line being least affected, despite a three-fold increase in PIMO uptake observed in plateau cells relative to exponentially growing Na11+ cells. The uptake of PIMO may be related to the high melanin content of plateau-phase Na11+ cells and therefore this in vitro model may be useful for predicting the effects of agents such as PIMO towards melanotic melanomas in vivo.

Etanidazole↗

PubMed1993

Lack of correlation of human fibroblast radiosensitivity in vitro with early skin reactions in patients undergoing radiotherapy.

Fibroblasts from breast cancer patients were obtained as outgrowths in vitro from punch biopsies and their radiosensitivity tested in early passages. Skin erythema reactions in the same patients were also measured, as degree of redness using reflectance spectrophotometry. Measurements were taken before and during a 4-week radiotherapy treatment with electrons to the thoracic wall. Of 59 biopsies studied, radiosensitivity and erythema were concurrently studied in 32. In 24, evaluable data from both clinic and laboratory were obtained. A population growth assay in 96-well plates, using absorption of sulphur rhodamine B as the stain for cell numbers, showed good agreement with the colony-formation assay. Plating efficiencies and growth rates in the colony assay were higher using human serum in place of foetal calf serum. Cell survival curves with human serum were mostly exponential with little shoulder. The parameters of survival at 2 Gy (SF2) and the dose required to give 10% survival (D10) were used in the correlations with clinical data; these were 0.25 +/- 0.09 and 3.03 +/- 0.50 Gy, respectively. There was a strong correlation between these two survival curve parameters (r = 0.98). Skin redness was found to linearly increase with time during radiotherapy. The slope of the increase differed markedly from patient to patient, with a range of a factor approx. 10. No correlation was found between SF2 and erythema response in the 24 evaluable patients (r = 0.13, p > 0.5). A similar lack of correlation was found using D10 as the radiosensitivity parameter (r = 0.12, p > 0.5). These data indicate that fibroblast radiosensitivity measured in vitro cannot be used to predict erythema reactions to radiotherapy in breast cancer patients.

Breast Neoplasms↗

PubMed1994

Relationship between gamma-ray-induced G2/M delay and cellular radiosensitivity.

Seven human and rodent cell lines with markedly differing cellular radiosensitivities were examined by the anti-Br-dUrd antibody and flow cytometric method in order to measure the progression of S phase cells and their accumulation in the G2 phase of the cell cycle after gamma-irradiation. Exponentially growing cells were labelled with 10 microM BrdUrd for 2 h, gamma-irradiated, then washed and cultured at 37 degrees C. At 2-h intervals postirradiation, the cells were harvested and fixed for flow cytometric analysis. Two parameter distributions of BrdUrd content and DNA content were analysed. The time intervals for unirradiated labelled cells to progress from S to G2/M phase were about 450 min for the human squamous cell carcinoma cell lines SCC-12B.2 (D0 = 2.66 Gy), SQ-20B (D0 = 2.39 Gy) and SCC-61 (D0 = 1.07 Gy) as well as for wild-type CHO cells (D0 = 2.62 Gy). After irradiation with 2 Gy, SCC-12B.2, SQ-20B, CHO and human diploid AG1521 cells showed similar small G2/M delays (about 1 h), whereas, a G2/M delay of about 2.2 h occurred in radiosensitive SCC-61 cells and delays of 5.0-7.7 h were observed in two extremely radiosensitive mutant cell strains (human AT homozygote and CHO xrs-5 respectively). When the cells were irradiated with doses yielding similar levels of survival (about 10%), however, the duration of the G2/M delay was generally similar (2-4 h) in all seven cell lines indicating a parallel relationship between radiation-induced G2/M delay and cellular radiosensitivity. These results suggest that the delay time may be related to the level of unrepaired damage present in the cell as it approaches mitosis.

Animals↗

PubMed1994

Evidence for a positive correlation between in vitro radiosensitivity of normal human skin fibroblasts and the occurrence of subcutaneous fibrosis after radiotherapy.

A colony-forming assay of human skin fibroblast radiosensitivity was established in our laboratory and applied to primary skin biopsies from 12 women belonging to an unselected group of patients who received postmastectomy radiotherapy 10-12 years prior to this study. The aim was to investigate the relationship between in vitro radiosensitivity and the occurrence of subcutaneous fibrosis after radiotherapy. Early generations of normal skin fibroblasts in exponential growth were irradiated at room temperature at a high dose-rate to estimate the surviving fraction of colony-forming cells after single doses ranging from 1 to 8 Gy. A linear-quadratic cell survival curve was fitted to the data and from these fits the surviving fraction at 3.5 Gy (SF3.5) was estimated. Replicate experiments of different cell generations were made to validate the assay, and the between-patients variability was significantly larger than the assay variability for both SF2(p = 0.002) and SF3.5 (p = 0.04). Patients were treated in the period 1978-1982 with a dose per fraction between 2.7 and 3.9 Gy, a total of 12 fractions at two fractions per week. They were evaluated with respect to the occurrence of marked subcutaneous fibrosis in a total of 36 independent treatment fields. In each treatment field the total dose and dose per fraction at the relevant dosimetric reference depth as well as the length of follow-up were recorded. A previously derived LQ mixture model was applied to these data in order to determine the probability of marked fibrosis in that particular field. From this probability and the actually observed fibrosis, the excess risk of fibrosis was calculated, and this was averaged over the three treatment fields to obtain a single measure of clinical radiosensitivity. Increasing values of SF3.5 were statistically significantly correlated with decreasing probabilities of developing subcutaneous fibrosis (p = 0.014, Spearman's rank correlation test). Thus, this pilot study has demonstrated a positive correlation between in vivo radiosensitivity and normal skin fibroblasts and the clinical expression of subcutaneous fibrosis.

Breast Neoplasms↗

PubMed1995

Dependence of fluorodeoxyuridine-mediated radiosensitization on S phase progression.

Recent evidence casts doubt on the hypotheses that fluoropyrimidine-mediated radiosensitization is related to cytotoxicity or to cell cycle redistribution into the G1/S boundary. We hypothesized that cells that are capable of progressing into S phase in the presence of fluorodeoxyuridine may also be more susceptible to radiation-induced damage. To test this hypothesis, fluorodeoxyuridine (FdUrd)-treated HT29 human colon cancer cells were separated by centrifugal elutriation into four fractions (1-4) containing a range of cells from those at the G1/S boundary (fraction 1) to those which had progressed approximately 11% into S phase (fraction 4). We found that fraction 4 cells showed significantly greater radiosensitization than fraction 1 cells. We also compared the effects of fluorodeoxyuridine on HT29 and SW620 human colon cancer cells. We found that, in contrast with HT29 cells, SW620 cells arrested at the G1/S boundary and were minimally radiosensitized. Finally, we found that an increase in sensitivity was correlated with a decrease in the rate of repair of DNA double-strand and single-strand breaks (assessed by asymmetric field inversion gel electrophoresis and alkaline elution respectively). These findings are consistent with the hypothesis that fluorodeoxyuridine-mediated radiosensitization depends on S phase progression and a decreased ability to repair radiation-induced DNA damage.

Cell Separation↗

PubMed1995

Tumour oxygenation, radiosensitivity, and necrosis before and/or after nicotinamide, carbogen and perflubron emulsion administration.

Hypoxia is one of the factors involved in tumour resistance to radiotherapy. One way to improve tumour oxygenation is to use oxygen carriers such as perflubron emulsion plus carbogen or vasoactive drugs such as nicotinamide. The perflubron emulsion and carbogen act mainly on hypoxia caused by limited diffusion of oxygen; nicotinamide acts mainly on acute hypoxia. The aim was to correlate radiosensitivity and pO2 measurements (computerized pO2 histograph) after nicotinamide, perflubron emulsion and carbogen administration, and to determine the role of necrosis in this correlation. Two human tumour xenografts (HRT18, Na11 +) and one rodent tumour (EMT6) were used. Clonogenic assays and pO2 measurements were performed under similar conditions. The radiosensitization and oxygenation levels increased with all treatments. The maximal effects were found with the combination of nicotinamide (1 g/kg), perflubron emulsion and carbogen. A correlation between the radiosensitization and the pO2 measurements was found for the three cell lines with a cut-off point of 10 mmHg. The presence of necrosis could explain the low pO2 (< 2 mmHg) found even when complete radiosensitization was observed.

Animals↗

PubMed1995

Mechanisms of radiosensitization in iododeoxyuridine-substituted cells.

The radiosensitization caused by iododeoxyuridine (IdU)-substitution of thymidine in V79-171 cells is decreased by the presence of acetone during irradiation. Acetone, at 1 mol dm-3, removes almost all the increase in double strand breaks (dsbs) caused by IdU substitution, but removes only about two-thirds of the enhancement in killing. Similar observations were made with BrdU-substituted cells. The decrease in cell radiosensitization coincides with the removal of the additional dsbs. The protection afforded by acetone is assumed to be due to its scavenging of hydrated electrons, thought to be the active species causing enhanced DNA damage in the presence of halogenated pyrimidines. The residual component of IdU radiosensitization, which could not be removed by treatment with acetone, is manifest largely as a shoulder effect (Dq) and may be due to either a subset of non-scavengable, lethal dsbs and/or the influence of IdU on the fixation of potentially lethal damage. This study further demonstrates that halogenated pyrimidine-mediated radiosensitization consists of at least distinct components each associated with a different phenomenon.

Acetone↗

PubMed1995

A comparison of the radiosensitivity of lymphocytes from normal donors, cancer patients, individuals with ataxia-telangiectasia (A-T) and A-T heterozygotes.

The aim was to determine whether peripheral blood lymphocytes can be used retrospectively to detect hypersensitivity to radiation in breast cancer patients who had exhibited severe reactions to radiotherapy. Blood samples were obtained from patients who developed both acute and late complications. For comparison, samples were also taken from a group of normal individuals, ataxia-telangiectasia (A-T) patients, A-T gene carriers and breast cancer patients previously treated with radiotherapy who failed to develop treatment-related complications. Radiosensitivity was assessed using a limiting dilution clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Following HDR irradiation, only lymphocytes from individuals with A-T were significantly more radiosensitive than those from normal donors. In contrast, at LDR, lymphocytes from A-T heterozygotes and breast cancer over reactors were also, on average, more sensitive than those from normal donors. Lymphocytes from breast cancer patients treated with radiotherapy without developing complications showed no significant differences in radiosensitivity compared with normals. This work has shown that peripheral blood lymphocytes from cancer patients who suffered severe reaction to radiotherapy are, on average, more radiosensitive than those from normal donors, and suggests that lymphocytes may be useful in the future for the development of rapid predictive assays for normal tissue tolerance to radiotherapy.

Ataxia Telangiectasia↗

PubMed1996

Radiosensitivity of human breast cancer cell lines of different hormonal responsiveness. Modulatory effects of oestradiol.

Treatments which inhibit or retard progression of the cell through the cell cycle have been reported to reduce the effectiveness of ionizing radiation by increasing cellular radioresistance. We studied cellular radiosensitivity and radiation-induced DNA damage (double-strand break, dsb) in both hormone-sensitive and non-sensitive human breast cancer cell lines. After 72h of culture in an oestradiol-deprived medium, MCF-7 BUS and T47D B8 breast cancer cells showed a significant delay in growth, whereas no effect was seen in EVSA-T cell line. In oestradiol-free medium, MGF-7 BUS cells were arrested mainly in G(zero)/G1 phase (85-90% in G(zero)/G1, 5-7% in S, and 6-8% in G2/M). The growth-delayed MCF-7 BUS cells showed reduced radiosensitivity (survival fraction at 2 Gy, SF2 = 63%; initial DNA damage 1.00 dsb/Gy/DNA unit) in comparison with proliferating cells (SF2 = 33%, initial DNA damage 2.70 dsb/Gy/DNA unit). The radio-protective effect of oestrogen deprivation was abolished by rescuing MCF-7 cells with oestrogen-containing medium. At 24h after rescue, MCF-7 BUS cells reached a cell cycle distribution close to that found under standard culture conditions and their radiosensitivity was correspondingly increased (SF2 = 40%, DNA damage = 2.52 dsb/Gy/DNA unit). Our findings indicate that: (1) sensitivity to radiation and the proportion of proliferating cells are probably related, and (2) differences in radiosensitivity reflect differences in radiation-induced DNA damage.

Breast Neoplasms↗

PubMed1997

Radiosensitivity and double-strand break rejoining in tumorigenic and non-tumorigenic human epithelial cell lines.

Radiosensitivity and repair of DNA damage induced by ionizing radiation and restriction enzymes were investigated in three human epithelial cell lines: two tumorigenic squamous carcinoma cell lines (SCC-4 and SCC-25), and a non-tumorigenic epidermal keratinocyte cell line (RHEK-1). Sensitivity to ionizing radiation was determined using a clonogenic cell survival assay, which showed SCC-4 to be more radiosensitive than SCC-25 and RHEK-1, which in turn displayed about equal sensitivity. Using DNA precipitation under alkaline conditions for the analysis of induction and repair of DNA single-strand breaks (ssb), an increased level of ssb induction was found for SCC-4 while the efficiency of ssb repair was about equal in all three cell lines. Using pulsed-field gel electrophoresis (PFGE) for the measurement of induction and repair of DNA double-strand breaks (dsb), no consistent differences were detected between the three cell lines. A plasmid reconstitution assay was used to determine the capacity to rejoin restriction enzyme-induced dsb in whole-cell extracts prepared from the three cell lines. In these experiments, dsb rejoining was shown to be significantly reduced in the most radiosensitive SCC-4 cell line while it was about equal in RHEK-1 and SCC-25. The results indicate that plasmid reconstitution in cell-free extracts is a sufficiently sensitive assay to detect differences in repair capacity among tumour cell lines of different radiosensitivity which remain undetectable by DNA precipitation and PFGE.

Amino Acid Sequence↗

PubMed1998

DNA damage induction and tumour cell radiosensitivity: PFGE and halo measurements.

PURPOSE: To test whether induction of DNA damage is correlated with tumour-cell radiosensitivity. MATERIALS AND METHODS: Initial DNA damage caused by X-irradiation was measured in ten human tumour cell lines, which largely differed in radiosensitivity, using either the pulsed-field gel electrophoresis assay or the halo technique. RESULTS: None of the parameters of DNA damage correlated with any parameter of cellular radiosensitivity. This was not only true when the analysis was performed on all data but also when the analysis was performed after separating the cell lines into radioresistant and sensitive groups. Even when differences in chromosome number, ploidy and cell cycle distribution were taken into account, no significant correlations were obtained. CONCLUSIONS: Contrary to previous suggestions, differences in the number of double-strand breaks induced or chromatin-related 'presentation' of DNA lesions, measured by pulsed-field gel electrophoresis or halo respectively, are generally not the dominant factors determining tumour-cell radiosensitivity.

Cell Survival↗

PubMed1998

Cytotoxic effect of paclitaxel (taxol) either alone or in combination with irradiation in two rat yolk sac tumour cell lines with different radiosensitivities in vitro.

PURPOSE: To investigate the differences between two rat yolk sac tumour cell lines with different radiosensitivities in paclitaxel sensitivity and in the sensitizing effects of paclitaxel in combination with irradiation. MATERIALS AND METHODS: NMT-1 is a parent radiosensitive cell line and NMT-1R is a variant radioresistant cell line. RESULTS: Clonogenic assay demonstrated almost the same paclitaxel sensitivity with Do of 5.15 nM in NMT-1 and 5.02 nM in NMT-1R. Many apoptotic cells and DNA ladder formations were observed at 24 h after exposure to paclitaxel in both cell lines. The incidence of DNA fragmentation after 24 h exposure to 20 nM paclitaxel was 12.4 +/- 3.3% for NMT-1, and 13.0 +/- 1.9% for NMT-1R. Paclitaxel showed a supra-additive effect in combination with irradiation in both cell lines at 12 h after paclitaxel treatment only when the accumulation of cells in the G2/M phase reached its peak. CONCLUSIONS: Paclitaxel had the same cytotoxic effect in two cell lines with different radiosensitivity due to the induction of apoptosis. A supra-additive effect to radiation was observed with 12 h pretreatment in both cell lines. Paclitaxel may be effective for tumours with a component of different radiosensitivity in combination with irradiation.

Animals↗

PubMed1982

Low dose radiosensitivity of alloimmune cytotoxic T cells.

Low dose radiosensitivity of in vitro generated alloimmune murine cytotoxic T lymphocytes (CTL) was studied. It appears that a subset of CTL exists that can be killed with 10-25 rad of x rays. These radiosensitive CTL are Lyt-1,2+ T lymphocytes. Analyses of cytotoxicity by chromium release assays indicate that the radiosensitive CTL are present in responder spleen cell cultures from all strains of mice tested. The generation of these effector cells is most pronounced in animals of the C57BL background. The mechanism of low dose radiosensitivity appears to be interphase death.

Animals↗