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Biomedical subjects

G G Steel

Publications and source records attributed to G G Steel.

At least 55 records · Page 3Linked to original sources
PubMed1989

Recovery kinetics deduced from continuous low dose-rate experiments.

Information on the rate of recovery from potentially lethal damage can be obtained from the analysis of the radiation dose-rate effect. Two mathematical models are useful in this respect: the Lethal-Potentially. Lethal (LPL) model of Curtis and the Incomplete Repair (IR) model of Thames. Full cell-survival curves are required at three or more dose rates in order to make a reliable analysis. Studies on human tumour cell lines yield values for recovery half-time in the range 0.1 to 0.9 h, and for each cell line the half-time found in this way is shorter than that obtained from a split-dose experiment. This result may imply that cellular recovery is a multi-component or a saturable process.

Animals↗
PubMed1989

High intrinsic radiosensitivity of a newly established and characterised human embryonal rhabdomyosarcoma cell line.

A new human rhabdomyosarcoma cell line (HX170c) has been established from a paratesticular embryonal tumour in a 5-year-old male. The cells grew as an adherent monolayer with a doubling time of 32 h and showed pleomorphic features. Intermediate filament analysis revealed the line to be mesenchymal in origin (reactivity to vimentin and desmin antibodies). The line was tumorigenic in nude mice, possessed elevated levels of creatine phosphokinase (mainly of the MM isoenzyme form) and had a near diploid mean chromosome number of 50. In vitro cell cloning determinations gave colony forming efficiencies of 0.01% in soft agar and 24% in a monolayer anchorage-dependent assay. Radiosensitivity determinations using a monolayer clonogenic assay with feeder layer support showed the cells to be among the more radiosensitive human tumour cell types (surviving fraction at 2 Gy of 0.26) that have been investigated. Furthermore, experiments utilising continuous low dose rate radiation at 3.2 cGy min-1, showed that, under these experimental conditions, the cells possessed only a very low capacity to recover from radiation-induced damage (dose reduction factor at 1% cell survival of 1.07 for 150 versus 3.2 cGy min-1). As other human tumour cells of an embryonal cell origin (e.g. neuroblastoma and germ cell tumours of the testis) have also been shown to be radiosensitive it appears that sensitivity to radiation may be a common property of this group of tumours.

Animals↗
PubMed1989

Recovery from radiation damage in human squamous carcinoma of the cervix.

The radiobiology of human carcinoma of the cervix has been investigated using five recently established cell lines. By means of an in vitro clonogenic assay, cell survival has been determined at dose-rates of 150, 3.2 and 1.6 cGy/min, and, in addition, split-dose experiments have been performed. Using approximately isoeffective doses (1 per cent cell survival), the amount of recovery observed using dose-rate and split-dose experiments has been correlated with the surviving fraction at 2 Gy (SF2 value) and the parameter alpha from the acute cell survival curves for the five lines. Two lines were radiosensitive, possessing significantly lower SF2 values (p = 0.03), and, at these isoeffect doses, showed significantly less sparing at low dose-rate (p = 0.012) and less split-dose recovery (p = 0.0096) than the three remaining cell lines. In general, the results indicate a good correlation between split-dose recovery-ratio, dose sparing achieved at low dose-rate compared to high, and SF2 value, and an inverse correlation with the alpha value derived from fitting dose rate dependence data to the incomplete-repair model of Thames. These observed differences in radiosensitivity within one human tumour type indicate the possible value of predictive testing of intrinsic radiosensitivity in the radiotherapy of carcinoma of the cervix.

Carcinoma↗
PubMed1989

The radiobiology of human cells and tissues. In vitro radiosensitivity. The picture has changed in the 1980s.

Substantial developments have been made during the 1980s in the radiobiology of human tumours, in particular in studies of the radiosensitivity of human tumour cells. It is now clear that tumour cells differ considerably in radiosensitivity, to an extent that by itself is capable of explaining the clinical response of tumours to radiotherapy. There also is evidence that the radiosensitivity of human tumour cell lines to low radiation doses correlates with clinical experience. Irradiation at low dose rate amplifies the differences between cell lines. In conjunction with mathematical modelling, a study of the dose-rate effect also allows a distinction to be drawn between repairable and non-repairable damage. The differences seen between cell lines at low acute doses or low dose rates are associated with the non-repairable component. The most radiosensitive cell lines have a steep component of non-repairable damage and they give the impression of being recovery-deficient; this may, however, be incorrect for when evaluated at constant dose levels recovery is found to increase with increasing radiosensitivity. This leads to the view that recovery from radiation damage may reflect the amount of recoverable damage inflicted rather than the 'capacity' of the cells to recover.

Cell Line↗
PubMed1988

The search for therapeutic gain in the combination of radiotherapy and chemotherapy.

The literature on combined treatment with radiation and cytotoxic drugs in experimental tumours and normal tissues of laboratory animals is reviewed in the context of the four previously proposed mechanisms whereby a therapeutic advantage might be gained. There is evidence for strong time-dependent processes occurring in some normal tissues. In tumours, the evidence for this is much weaker and there is considerable disparity among experimental tumours in optimum timing. This review leads to the conclusion that the clinical use of drug-radiation combinations should not be based on an anticipated beneficial interaction; gain will most probably come from the best radiotherapy and the best chemotherapy given as far as possible independently. Deleterious interactions can be reduced by allowing a gap of some weeks between chemotherapy and radiotherapy and by avoiding drugs that are known to enhance radiation damage to the normal tissues that are irradiated.

Animals↗
PubMed1988

Differences in radiation response among human cervix carcinoma cell lines.

The radiobiological properties of five newly established carcinoma of the cervix cell lines have been determined. By means of an in vitro clonogenic assay, survival curves were compared at radiation dose rates of 150, 3.2 and 1.6 cGy/min. In terms of both acute radiosensitivity and the extent of low dose-rate sparing, large differences existed among the lines. Two of the lines, HX151c and HX160c, were radiosensitive (surviving fractions at 2 Gy of 0.23 and 0.33 respectively) and showed little radiation recovery capacity during protracted irradiation, whereas the remaining three lines had much higher surviving fraction at 2 Gy (up to 0.6) and showed considerable low dose-rate sparing. The data were well fitted by the Incomplete Repair model of Thames; repair half times ranged from 0.25 to 5.7 h. These findings indicate that large differences in intrinsic radiation recovery capacity exist within this tumour type, differences which emphasise that predictive testing of intrinsic radiosensitivity may be of clinical value in this disease.

Carcinoma, Squamous Cell↗
PubMed1988

Inhibition of recovery from damage induced by ionizing radiation in mammalian cells.

Recent studies indicate the importance for radiotherapy of the inherent radiosensitivity of tumour cells in the low-dose region; a region where recovery is probably almost complete. Improvements in radiotherapy may therefore depend on the search for specific inhibitors of cellular recovery. This review summarizes data from studies in which use was made of a variety of mammalian, including human cell systems, where attempts have been made to inhibit recovery using chemical agents. Inhibition of sublethal damage repair, potentially lethal damage repair and low dose-rate sparing has been observed to varying extents by several agents including those thought to act by interfering with DNA repair processes (e.g. ara-C, 3-aminobenzamide) differentiation-inducing agents (e.g. N-methylformamide), halogenated pyrimidines (e.g. iododeoxyuridine), caffeine and chemotherapeutic agents (e.g. adriamycin). No individual agent stands out as exerting an exceptionally dramatic effect on recovery. However, of the agents used clinically, cis-platinum appears to hold some promise, while iododeoxyuridine, N-methylformamide, beta ara-A and caffeine all appear to inhibit to some extent the recovery of ionizing radiation-induced damage. There is an urgent need for further study to determine, in particular, relative effects in tumour versus normal cell types and whether any agents found to be effective in vitro show similar effects in vivo.

Animals↗
PubMed1988

Growth and chemotherapy of a human germ-cell tumour line (GCT 27).

The human germ-cell tumour cell line GCT 27 growing as subcutaneous xenograft tumours in male nude mice was used in the 4th and 5th passage to study chemotherapeutic drug responses. Recipient mice received 5 Gy whole body irradiation immediately before tumour transplantation. The median take rate was 62% (range 39-73%) and the median volume doubling time 14 days (range 7-28 days). For bleomycin, cisplatin and carboplatin a clear dose response for growth delay was observed. Bleomycin caused substantial weight loss at doses above 75 mg/kg whereas good response to cisplatin was obtained without serious toxic effects. Vinblastine and etoposide exerted no effect when given in non-toxic doses. The response to etoposide was not improved either by fractionated treatment or by combination with verapamil. However, the combination of 20 mg/kg etoposide and 2 mg/kg cisplatin, which when given alone were ineffective, led to a growth delay that was equal to that observed following the administration of higher cisplatin doses. This effect may be explained by the fact that etoposide, as an inhibitor of DNA-topoisomerase II, may interfere with the repair of DNA interstrand cross-links caused by cisplatin.

Animals↗
PubMed1988

Differential radiosensitization by the poly(ADP-ribose) transferase inhibitor 3-aminobenzamide in human tumor cells of varying radiosensitivity.

Four newly-established human tumor cell lines, have been irradiated at dose rates of 150 and 3.2 cGy/min to compare their capacity to repair radiation damage. They included a neuroblastoma, a germ-cell carcinoma of the testis, a large cell carcinoma of the lung, and a carcinoma of the cervix. The four lines varied in their sensitivity to high dose-rate irradiation, with the neuroblastoma being most radiosensitive and the lung and cervix tumors the most radioresistant. The extent of dose sparing associated with lowering the dose rate to 3.2 cGy/min was similar in three of the lines but somewhat greater in the case of the cervix carcinoma cell line. The presence of non-toxic concentrations of the poly(ADP-ribose) transferase inhibitor, 3-aminobenzamide (3-AB), enhanced the response of 3 of the 4 tumors to irradiation; it failed to modify the sensitivity of a lung carcinoma cell line. The extent of sensitization was generally similar at high and low dose rate. Measurement of poly(ADP-ribose) transferase activity in control and irradiated cells showed the neuroblastoma cells to contain much higher initial levels than the other three lines but there were no significant differences in the extent of stimulation in enzyme levels after irradiation. Survival curves obtained at low dose-rate help define the initial slope of the acute curve and it appears that 3-AB may exert a differential effect among human tumors in modifying this component.

Benzamides↗
PubMed1988

Chemotherapy-radiation interactions in human cervix carcinoma xenografts.

The combination of irradiation and four agents of clinical interest in the treatment of cervix carcinoma (bleomycin, etoposide, cisplatin and ifosfamide) have been investigated using two human cervix carcinoma xenografts in nude mice. As a model of clinical brachytherapy regimes, radiation was administered at a continuous low dose rate of 5 cGy min-1 to a total dose of 9 or 12 Gy. No substantial enhancement in tumour growth delay over that observed for radiation alone was observed with bleomycin, etoposide or cisplatin. Ifosfamide, however, led to substantial additional growth delay, an effect which was lost when irradiation was administered at a higher dose rate of 70 cGy min-1. As dose-rates of around 5 cGy min-1 allow greater repair of radiation damage than at the higher dose-rate without significant cell cycling or repopulation, it is possible that ifosfamide may act as an inhibitor of repair processes in this model. It would be of interest to evaluate the role of ifosfamide and brachytherapy regimes in the clinical treatment of carcinoma of the cervix.

Animals↗
PubMed1988

Modification of radiation dose-rate sparing effects in a human carcinoma of the cervix cell line by inhibitors of DNA repair.

The in vitro cell survival of a human cervix carcinoma cell line (HX156c) has been assessed using 60Co gamma-rays administered at either high (150 cGy/min) or low (3.2 cGy/min) dose rate. Recovery during low dose-rate irradiation was observed; the dose reduction factor at 10(-2) cell kill for 150 versus 3.2 cGy/min was around 1.3. An insight into the possible underlying mechanisms of this recovery process has been investigated by addition of non-toxic concentrations of various agents thought to inhibit eukaryotic DNA repair. Agent were added 2 h prior to irradiation and removed after 24 h exposure. Differential effects among the inhibitors were observed; aphidicolin had no effect on cell survival, novobiocin, hydroxyurea and 3-aminobenzamide reduced survival by a similar extent at both dose rates, beta-ara A and caffeine reduced survival to a greater extent during low dose-rate irradiation. beta-ara A and caffeine seemed to exert their effects mainly by increasing the alpha component of the acute survival curve. Since survival curves obtained at dose rates of around 3 cGy/min help define a dominant component of the initial slope of the acute curve we have demonstrated that beta-ara A and caffeine modify the initial slope, probably by inhibiting DNA repair processes involved in the sparing of tumour cells during protracted irradiation.

Aphidicolin↗