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Biomedical subjects

G G Steel

Publications and source records attributed to G G Steel.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1988

Induction and rejoining of DNA double-strand breaks in human cervix carcinoma cell lines of differing radiosensitivity.

Five recently established cell lines of human carcinoma of the cervix of varying radiosensitivity have been used to determine whether the induction or rejoining of DNA double-strand breaks (dsb) shows any correlation with radiosensitivity or radiation recovery capacity. Double-strand DNA breaks have been measured using neutral filter elution at pH 9.6. The number of breaks induced immediately after irradiation with doses of 10 to 40 Gy 60Co gamma rays appeared to show some correlation with radiosensitivity particularly after 10 Gy; the two more radiosensitive lines incurred more breaks than the more radioresistant lines. In addition, the shape of the induction curve with dose was linear for the two sensitive lines but curvilinear for the resistant lines. Despite the dose scales being different, this mirrored their respective cell survival curve shapes. After 30 or 50 Gy irradiation, rejoining of breaks appeared to be rapid and almost complete within 60 min at 37 degrees C for the three resistant lines. However, for the sensitive lines, one line (HX160c) in particular exhibited a reduced rate of dsb rejoining. In addition, a residual level of dsb was present in this line even after allowing rejoining for 3 h. While induction and rejoining of DNA dsb therefore appears to be a factor in determining radiosensitivity, at doses relevant to cellular survival (up to 10 Gy), the greater induction of DNA dsb in radiosensitive lines may play a significant role in determining the cellular response to ionizing radiation.

Cell Line↗
PubMed1988

Inhibition of radiation dose-rate-sparing effects in human tumor cells by 3-aminobenzamide.

The capacity of two recently established human tumor cell lines (a germ cell carcinoma of the testis and a squamous cell cervical carcinoma) to repair radiation damage has been determined by assessing in vitro cell survival over the dose-rate range of 150-1.6 cGy/minute. Survival after irradiation at a high dose rate (150 cGy/min) showed that the cervical carcinoma was more radioresistant. A dose-sparing effect was observed at low dose rates (3.2 and 1.6 cGy/min), compared to the high dose rate, to a similar extent in both cell lines. In addition, 3-aminobenzamide added 2 hours prior to and removed 18 hours after irradiation caused a small but similar increase in cell kill with the high dose rate in both cell lines. It also steepened the survival curves at low dose rates. Since the survival curves obtained at 1.6 and 3.2 cGy/minute help to define a dominant component of the initial slope of the acute curve, we conclude that 3-aminobenzamide can act as a modifier of this component.

Benzamides↗
PubMed1987

Characterization of four new cell lines derived from human squamous carcinomas of the uterine cervix.

Four continuous cell lines were established from 15 biopsies of human squamous carcinomas of the uterine cervix, two from women less than 35 years old. All four lines grew as adherent monolayers and had epitheloid morphology. All required initial 3T3 feeder layer support and hydrocortisone and insulin for growth and have now been grown in vitro for at least 12 months. The individual lines possessed unique isozyme patterns and were distinct from the HeLa cell line. All were tumorigenic in nude mice. In vitro colony forming efficiencies ranged from 2 to 30% in a monolayer anchorage dependent assay but were only from 0.0025 to 0.6% when assayed in soft agar. The lines were all aneuploid with mean chromosome numbers ranging from 71 to 75. Analysis of intermediate filament expression showed that all lines were positive for cytokeratin expression and two were positive for vimentin expression. These low-passage cell lines represent a panel of new in vitro models of carcinoma of the cervix. They should be useful for the investigation of chemosensitivity, of the involvement of human Papillomavirus in this disease, and as models of squamous cell differentiation.

Adult↗
PubMed1987

Development of MeCCNU-resistance in clonally derived lines of Lewis lung carcinoma.

The development of resistance to MeCCNU in four clonal lines of Lewis lung carcinoma derived from lung colonies has been examined. Treatment of the clones with 15 mg/kg MeCCNU once in each in vivo passage resulted in a rapid reduction in tumour responsiveness to this drug. This shows that MeCCNU resistance can arise at rates which may be applicable in spontaneous tumours and their metastases. Karyotypic heterogeneity was evident very early after isolation of the clones and this has potentially important implications for the experimental use of clones and for the features of metastatic disease. Karyotype analysis of one of the clones at each passage suggested that development of resistance was associated with the selection of a single sub-population of tumour cells but the kinetics of resistance development cannot be totally explained in terms of this simple selection.

Animals↗
PubMed1987

The dose-rate effect in human tumour cells.

The radiation response of 12 cell lines derived from a variety of human tumours has been investigated over the dose-rate range from 150 to 1.6 cGy/min. As the dose rate was lowered, the amount of sparing varied widely; in 2 cell lines it was zero, in the other cell lines the dose required for 10(-2) survival ranged up to twice the value at high dose rate. Low dose-rate irradiation discriminates better than high dose rate between tumour cell lines of differing radiosensitivity. The data are equally well fitted by two mathematical models of the dose-rate effect: the LPL model of Curtis and the Incomplete Repair model of Thames. Analysis by the LPL model leads to the conclusion that the theoretical radiosensitivity in the total absence of repair was rather similar among the 7 cell lines on which this analysis was possible. What differs among these cell lines is the extent of repair and/or the probability of direct infliction of a non-repairable lesion. Recovery from radiation damage was also examined by split-dose experiments in a total of 17 human tumour cell lines. Half-time values ranged from 0.36 to 2.3 h and there was a systematic tendency for split-dose halving times to be longer than those derived from analysis of the dose-rate effect. This could imply that cellular recovery is a two-component process, low dose-rate sparing being dominated by the faster component. The extent of low dose-rate sparing shows some tendency to correlate with the magnitude of split-dose recovery; in our view the former is the more reliable measure of cellular recovery. The clinical implication of these studies is that some human tumour types may be well treated by hyperfractionation or low dose-rate irradiation, while for others these may be poor therapeutic strategies.

Cell Line↗
PubMed1987

Effect of dose-rate on the survival of murine spermatogonia following 60Co gamma-irradiation.

The survival of murine clonogenic stem and differentiated spermatogonia was assessed by counts of repopulating tubules in histological sections at 35 days and counts of testicular sperm-heads at 29 days respectively, following irradiation delivered at five dose-rates (1.1, 2.5, 5, 11 and 112 Cgy X min-1). For stem spermatogonia, a significant increase in cell survival accompanied the reduction in dose-rate, and this was characterized by an increase of the Do for the derived survival curves from 2.86 +/- 0.29 Gy at 112 cGy X min-1 to 4.46 +/- 0.45 Gy at 1.1 cGy X min-1. The data were analysed using two mathematical models for repair at varying dose-rates, the LPL model of Curtis and the incomplete repair model of Thames. Using these models the half-time for repair was estimated to lie between 15 and 25 min. No dose-rate effects were observed for the differentiated spermatogonia. The sparing of stem spermatogonia at reduced dose-rate, may have implications for the future fertility of men treated with low dose-rate total body irradiation (TBI).

Animals↗
PubMed1987

Radiation damage repair capacity of a human germ-cell tumour cell line: inhibition by 3-aminobenzamide.

The capacity of a human germ-cell tumour line to repair radiation damage has been investigated by means of a clonogenic assay. Dose-rate dependence studies, split-dose experiments and experiments designed to measure repair of potentially lethal damage have been performed. The cells showed some ability to repair radiation-induced damage in all three types of experiment. An attempt has been made to understand the possible cellular mechanisms of these repair processes by the use of 3-aminobenzamide (3-AB), an agent thought to act by inhibition of ADP-ribosylation. 3-AB added 2 h prior to and removed 18 h after irradiation at a non-toxic dose to unirradiated cells caused a small but consistent increase in cell kill with acute (150 cGy min-1) irradiation, largely involving a reduction in the shoulder region of the survival curve, but had a greater effect in increasing cell kill at a dose rate of 7.6 cGy min-1 and an even greater effect at a dose rate of 1.6 cGy min-1. When 3-Ab was present 2 h prior to the first dose and between two equal doses in a split-dose experiment, inhibition of split-dose recovery was observed. In addition, some inhibition of potentially lethal damage recovery was observed with 3-AB. A possible role for poly(ADP-ribosylation) is thus implicated in the repair of radiation-induced damage of this human tumour cell line during continuous low dose rate or fractionated radiation schedules, although other effects of 3-AB on respiratory metabolism and/or purine synthesis cannot be eliminated as the cause of the observed inhibitory effects.

Benzamides↗
PubMed1987

The response of murine stem spermatogonia to radiation combined with 3-aminobenzamide.

The influence of 3-aminobenzamide (3-AB) on the radiation response of the stem spermatogonia of the CBA mouse has been investigated. Doses of 3-AB from 66 to 450 mg/kg, administered 1 h before irradiation, significantly enhanced stem-cell killing. Enhancement was observed when 3-AB (450 mg/kg) was given up to 5 h before, but not if administered after, irradiation. When radiation was delivered at a lower dose rate (5 cGy/min compared to 180 cGy/min) significant dose sparing was achieved for radiation alone. Pretreatment with 3-AB resulted in slightly less enhancement at the low dose rate than at the high. Split-dose studies (9 Gy total dose) with radiation alone resulted in a recovery ratio of 1.4-1.5. Administration of 3-AB before the first dose resulted in a similar recovery ratio, but if given immediately after the first dose the ratio was smaller. Pretreatment of mice with the radiosensitizer RSU-1069 indicated that at least some of the stem cells were radiobiologically hypoxic. We suggest therefore that the enhancement of spermatogonial stem-cell killing by 3-AB is not entirely due to inhibition of repair processes but may also involve modification of the oxygen status of the testis.

Animals↗
PubMed1987

Split-dose and low dose-rate recovery in four experimental tumour systems.

The radiation dose-rate effect has been investigated in three murine tumour cell systems (MT carcinoma, Lewis lung tumour, B16 melanoma) and in the HX34 human melanoma xenograft taken directly from mice and irradiated in vitro. The four tumour types were remarkably similar in their radiation response characteristics, especially at low dose rate; the Lewis lung tumour tended to be the most radiosensitive at high dose rate. The data have been analysed using the Lethal-Potentially Lethal (LPL) model of Curtis and the Incomplete Repair (IR) model of Thames. The data are equally well fitted by both models. The most remarkable feature of these analyses is that both models lead to estimates for the half-time for recovery that are in the region of 0.1 h, considerably shorter than other published values. Split-dose experiments were also performed, taking care to keep the cells at 37 degrees C between exposures. In all cases the split-dose half times were longer than the values derived from dose-rate analysis and in the case of the Lewis lung and HX34 tumour lines the difference was by almost a factor of ten. The discrepancy between these estimates could be the result of biphasic cellular recovery.

Animals↗
PubMed1986

Survival of murine clonogenic stem spermatogonia following combined radiation and cytotoxic drug treatments.

The effects of combined radiation and cytotoxic drug treatments on the survival of murine clonogenic stem spermatogonia have been investigated using an in vivo clonogenic assay. Drug doses (BCNU, 15 mg/kg; cyclophosphamide (CY) 150 mg/kg, and procarbazine (PCB) 200 mg/kg) were chosen to kill a high proportion of differentiated spermatogonia, but no stem-cells, and were administered as single doses up to 14 days prior to or after 9 Gy of X rays. BCNU produced a moderate enhancement of damage (DEF, 1.0-1.3) that was relatively time-independent. Both CY and PCB demonstrated considerable enhancement of damage (DEF, 1.6 +/- 0.03, respectively) when administered 1 day prior to radiation, and also 3 days prior to radiation for PCB (DEF = 1.4 +/- 0.05). The enhancement of damage may have been caused by either a change in the shoulder width of the cell-survival curve, or additive cell-killing as indicated by a dose-response study.

Animals↗
PubMed1986

The effect of low dose-rate and cyclophosphamide on the radiation tolerance of the mouse lung.

Mice were given cyclophosphamide 30 mg/kg intraperitoneally before thoracic irradiation at high dose-rate (HDR, 100 cGy/min) or low dose-rate (LDR, 5 cGy/min). The development of pneumonitis was monitored by regular measurement of breathing rate. Peak rises in breathing rate occurred around 4-9 weeks in those given cyclophosphamide before irradiation, and around 14-16 weeks in those given radiation alone, regardless of dose-rate. The dose reduction factor (DRF = LDR/HDR ratio) for LDR irradiation was congruent to 1.8 but LDR sparing was abolished (DRF congruent to 1.0) when cyclophosphamide was given before irradiation.

Animals↗
PubMed1986

Dose-rate effects in the radiation response of four human tumour xenografts.

The radiation repair capability of four human tumour xenograft lines, two adenocarcinomas of the pancreas, an adenocarcinoma of the breast and a melanoma, has been investigated by means of a soft agar clonogenic assay. Dose-rate dependence studies at 150, 7.6 and 1.6 cGy/min and split-dose experiments, have been performed. Results indicate a good correlation between split-dose recovery and the dose-sparing achieved by irradiation at 1.6 cGy/min when compared to acute irradiation in 3 of the 4 tumour lines. The HX118 melanoma showed dose-sparing at dose-rates of 7.6 and 1.6 cGy/min and a substantial ability to perform recovery between split doses of radiation, whereas HX32, a pancreatic carcinoma, showed little dose-sparing and a correspondingly small degree of split-dose recovery. The HX99 breast carcinoma, was aberrant in showing the greatest split-dose recovery of the four lines but only a moderate extent of low dose-rate sparing. Data have been fitted by two recently described models for radiation dose-rate dependence; the incomplete repair model of Thames and the Lethal Potentially-Lethal (LPL) model of Curtis. Curves were fitted better by the Thames model which provided a good fit for data from 3 of the 4 xenografted human tumour lines. HX99 produced dose-rate dependence survival curves that were not well fitted by either model.

Adenocarcinoma↗
PubMed1986

Influence of timing of cytotoxic drug treatment on the response of murine clonogenic spermatogonia to X-irradiation.

The enhancement of radiation-induced stem spermatogonial cell killing by three cytotoxic compounds has been investigated using an in vivo clonogenic assay. Drug doses (carmustine (BCNU), 15 mg/kg; cyclophosphamide (CY), 150 mg/kg; procarbazine (PCB), 200 mg/kg) were chosen to kill a high proportion of differentiated spermatogonia but few stem-cells, as assessed by sperm-head counts (SHC) at 29 and 56 days respectively. Drug doses were administered up to 14 days prior to or after local irradiation with 9 Gy of 230 kVp X-rays. BCNU produced a moderate enhancement of damage that was relatively independent of time. Both CY and PCB produced a considerable enhancement of damage especially when administered 1 to 3 days before irradiation. Enhancement in the case of PCB consisted largely of a vertical displacement of the radiation dose-response curves, but with additional evidence for possible changes in slope.

Animals↗
PubMed1986

The acute in vitro and in vivo radiosensitivity of human lung tumour lines.

Eleven human lung tumour lines have been established in xenograft or tissue culture, and the responses to acute irradiation of the 10 lines which cloned in soft agar were assayed. In vitro radiosensitivity was evaluated using the multitarget and linear quadratic models of cell survival and the surviving fraction at 2 Gy. Significant differences in the response of the different cell types were found, the large-cell phenotype exhibiting radioresistance, and small-cell carcinomas and adenocarcinomas being radiosensitive. No differences in the capacity of the different tumour types to repair radiation damage were demonstrated. In vivo and spheroid response was modified by the effects of hypoxia and cell-contact phenomena. The results suggested that hyperfractionation would be useful in the clinical management of adenocarcinoma and small-cell carcinoma.

Animals↗
PubMed1986

Repair in the mouse lung during low dose-rate irradiation.

The thorax of CBA mice was exposed to 60Co gamma-rays at dose rates ranging from 100 to 2 cGy/min. Iso-effect doses (ED50) were calculated for early and late lung damage from dose-response curves for breathing rate and lethality. A continuous increase in tolerance for early radiation pneumonitis was seen as the dose rate was reduced, reaching a dose recovery factor (DRF) of 2.6 at 2 cGy/min. There was significantly less dose sparing with 2 cGy/min for the rise in breathing rate during expression of late damage (DRF = 2.1). The lower DRF compared well with that obtained from late measurements of pleural fluid levels. Comparison with fractionation experiments indicated incomplete repair at 2 cGy/min with further dose recovery expected at even lower dose rates or at doses per fraction below 200 cGy. Since the dose-rate dependence of damage to haemopoietic tissue is less marked, this study predicts an advantage of employing low dose-rate total-body irradiation (TBI) in the treatment of bone-marrow transplant patients. A further gain in the therapeutic index may be expected using a hyperfractionated regime with small doses per fraction.

Animals↗
PubMed1986

Lung damage after hemithoracic irradiation: dependence on mouse strain.

A comparative study was performed on CBA, C57Bl mice and their F1 hybrid cross (CBBF1) after right hemithorax irradiation using doses ranging from 15 to 35 Gy. A dose-dependent increase in breathing rate was observed, corresponding to the expression of radiation pneumonitis in the irradiated lung. The use of hemithoracic irradiation enabled this to be observed without any lethality. Results obtained from X-ray computerized tomography (CT), lung weight and histology complemented the breathing rate studies. CBA mice showed a peak response at 16 weeks followed by a decline in breathing rate coincident with a compensatory hypertrophy of the shielded left lung. The manifestation of radiation pneumonitis in C57Bl mice was considerably delayed, supporting previous findings on whole-thorax irradiated animals. The latent period in CBBF1 hybrid mice was intermediate between the parent strains.

Animals↗