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J H Peacock

Publications and source records attributed to J H Peacock.

At least 19 recordsLinked to original sources
PubMed1992

Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity.

The success of radiotherapy depends on the total radiation dose, which is limited by the tolerance of surrounding normal tissues. Since there is substantial variation among patients in normal-tissue radiosensitivity, we have tested the hypothesis that in-vitro cellular radiosensitivity is correlated with in-vitro normal-tissue responses. We exposed skin fibroblast cell lines from six radiation-treated patients to various doses of radiation and measured the proportions surviving. There was a strong relation between fibroblast sensitivity in vitro and normal-tissue reactions, especially acute effects. Assessment of radiosensitivity could lead to improved tumour cure rates by enabling radiation doses to be tailored to the individual.

Breast Neoplasms↗
PubMed1992

Heterogeneity of radiosensitivity in a human glioma cell line.

Sixteen clones were isolated from an early-passage human glioma cell line (IN859) and have been found to show variation in several biological characteristics including DNA content, modal chromosome number, and morphology. In addition, heterogeneity of radiosensitivity was detected: the doses that gave a surviving fraction of 0.01 varied by a factor of approximately 1.5. The most sensitive (clone 6) and the most resistant (clone 9) clones were selected for further study; their surviving fractions at 2Gy (SF2) were 0.37 and 0.64, respectively. When compared at a fixed radiation dose the sensitive clone surprisingly demonstrated greater split-dose recovery than the resistant clone; it also showed greater low dose-rate sparing.

Aged↗
PubMed1992

Differences in the level of DNA double-strand breaks in human tumour cell lines following low dose-rate irradiation.

It is now well accepted that differences exist in the intrinsic radiosensitivity of human tumour cells although the molecular basis of this is still unclear. Current evidence suggests that of the lesions induced in DNA by ionising radiation, double-strand breaks (DSB) are the most closely linked to cell death. In this study, levels of DSB were measured by neutral filter elution under conditions of both repair inhibition and maximum recovery and compared with clonogenic survival curves for high (HDR) and low dose-rate (LDR) irradiation in human carcinoma lines of differing radiosensitivity. Four human lung carcinoma lines were used, two small-cell (SCLC; HC12 and HX149) and two non-small cell lines (NSCLC; HX147A7 and HX148G7). Cell survival was measured by soft agar and monolayer colony-forming assays as appropriate and a large variation in sensitivity of the cell lines was seen (alpha values of 0.06 to 0.56 Gy-1). We have previously reported that the damage induced at high dose rate does vary in these cell lines but not in a way which correlates with their cell survival response [5]. Following irradiation to 15 Gy at low dose rate essentially no DSBs were detected in any of the four lines but at 70 Gy the more sensitive SCLC showed more residual damage than in the more radioresistant NSCLC lines. The prime determinant of the difference between the LDR and HDR damage curves is likely to be repair occurring during irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Survival↗
PubMed1992

Host cell reactivation of gamma-irradiated adenovirus 5 in human cell lines of varying radiosensitivity.

DNA repair processes play an important role in the determination of radiation response in both normal and tumour cells. We have investigated one aspect of DNA repair in a number of human cell lines of varying radiosensitivity using the adenovirus 5 host cell reactivation assay (HCR). In this technique, gamma-irradiated virions are used to infect cells and the ability of the cellular repair systems to process this damage is assayed by a convenient immunoperoxidase method recognising viral structural antigen expression on the cell membrane 48 h after infection. Reduced HCR was exhibited by radioresistant HeLa cells and by a radiosensitive neuroblastoma cell line, HX142. In contrast, an ataxia telangiectasia cell line, AT5 BIVA, did not show reduced HCR. On the basis of these results we can make no general conclusions about the relevance of HCR to cellular radiosensitivity. We have extended these studies to determine whether our cell lines exhibited enhanced viral reactivation (ER) following a small priming dose of gamma-radiation given to the cells before viral infection. No evidence for this phenomenon was found either in normal or tumour cell lines.

Adenoviruses, Human↗
PubMed1992

Cellular recovery in two sub-lines of the L5178Y murine leukaemic lymphoblast cell line differing in their sensitivity to ionizing radiation.

Cellular recovery was assessed in two sublines of L5178Y murine lymphoma cells of differing radiosensitivity (LY-S and LY-A4) using low dose-rate irradiation and split-dose experiments. No increase in cell survival was observed in the LY-S cell line until the dose-rate was reduced to 2 cGy/min, whereas in the LY-A4 cell line 20 cGy/min was low enough to detect changes in survival. The extent of this change, as assessed by dose reduction factors at 2 logs of cell kill, was greater in the LY-A4 cell line. Fitting these data with the incomplete repair model of Thames led to anomalous values for the half-time of repair. In split-dose experiments the maximum observed recovery ratio increased as a function of dose in a manner that is consistent with the linear-quadratic equation. As was found previously with radiosensitive human tumour cells, the LY-S cell line showed more split-dose recovery at any given dose than the LY-A4 cell line.

Animals↗
PubMed1992

The intrinsic alpha/beta ratio for human tumour cells: is it a constant?

The radiation response of 15 mammalian cell lines comprising 11 human tumour, two human fibroblast and two murine lymphoma cell lines, has been analysed using the linear-quadratic equation. As well as using conventional analysis of acute dose-survival curves to derive values for alpha and beta (termed alpha ac and beta ac), low dose-rate and split-dose experiments have been used to derive independent values of alpha and beta (alpha 1dr and beta RR), respectively. alpha 1dr provides a measure of irrecoverable damage, the magnitude of which agreed well with the initial slope of the acute survival curve for most cell lines. beta RR derived from split-dose experiments represents a unique measure of recovery for each cell line. Large differences were found between individual values of beta ac and beta RR, especially in the radiosensitive cell lines. Since beta RR is a functional measure of recovery we suggest that this is the more relevant parameter in studies of dose sparing. The most striking result of this analysis was found in considering the alpha/beta ratios. No relationship was observed between alpha ac and beta ac resulting in values of alpha ac/beta ac ranging from 1 to 175. In contrast a positive correlation was observed between alpha 1dr beta RR in the 11 tumour cell lines, giving an alpha/beta ratio of 9.4 +/- 1.8 Gy. This observation of the relative constancy of the ratio for human tumour cells leads to an hypothesis about the role of initial damage as a determinant of radiosensitivity.

Animals↗
PubMed1992

The inherent cellular sensitivity to 62.5 MeV(p----Be+) neutrons of human cells differing in photon sensitivity.

The inherent sensitivity of 20 human cell lines to the 62.5 MeV(p----Be+) clinical neutron beam at Clatterbridge, UK, has been assessed and compared to their sensitivity to 4 MeV photons. The survival curves of the cell lines following neutron irradiation were curvilinear, and the inherent neutron sensitivity varied by 4.5 fold (0.1 survival level) between the extreme values, in the cell lines studied. There was a strong correlation between the sensitivity of these human cells to photon and neutron irradiation. It was concluded that should these in vitro patterns occur in the clinic, the 4-fold variation in RBE and inherent sensitivity to neutrons could result in overall lower local control rates following fast neutron therapy than might be anticipated. It suggests the need for the development of predictive assays as a potential means of selecting tumours most appropriate for neutron therapy.

Cell Line↗
PubMed1990

Changes in membrane-bound and soluble molecular forms of acetylcholinesterase in mouse hippocampus after cholinergic denervation.

In order to observe acetylcholinesterase (AChE) and its distribution into soluble and membrane-bound molecular forms in cholinergically denervated hippocampus, AChE was analyzed in the hippocampus of adult mice with and without bilateral fornix lesions made by stereotactically positioned knife cuts. Homogenates from lesioned mice contained an average of 3% of choline acetyltransferase-specific activity, 12% of AChE-specific activity and 98% of protein compared to homogenates from controls. After lesioning, the relative proportion of membrane-bound G4 decreased from 77% to 56% of total AChE while soluble G4, membrane-bound G1-G2, and soluble G1-G2 each increased in relative abundance.

Acetylcholine↗
PubMed1990

Radiosensitivity, recovery and dose-rate effect in three human glioma cell lines.

The results of radiotherapy in the treatment of high-grade gliomas are disappointing. In this study three recently established cell lines from high-grade human gliomas have been found to exhibit a sensitivity that is at the resistant end of the spectrum of radiosensitivities seen in human tumour cells generally. The results support the view that inherent cellular radioresistance may be an important cause of failure in this disease. All three cell lines showed an increase in survival when the radiation dose rate was reduced. In split-dose experiments, recovery was found to increase with dose in a manner consistent with the predictions of the linear-quadratic equation.

Cell Line↗
PubMed1990

The radiation dose-rate effect in two human neuroblastoma cell lines.

The current use of targeted radiotherapy in the treatment of neuroblastoma has generated a requirement for further information on the radiobiology of these cells. Here we report on studies of the dose-rate effect in two human neuroblastoma cell lines (HX138 and HX142) and the recovery that they demonstrate in split-dose experiments. The sensitivity of the two cell lines to high dose-rate irradiation was confirmed. Surviving fractions at 2 Gy were 0.083 for HX138 and 0.11 for HX142. There was little evidence of a dose-rate effect above 2 cGy min-1 but significant sparing was seen at lower dose rates. Substantial recovery was seen in split-dose experiments on both cell lines, to an extent that was consistent with the linear quadratic equation. The data were used to derive values for the beta parameter of the linear-quadratic equation; the values for the neuroblastomas were higher than for any of the other human tumour cell lines that we have investigated to date. Thus, despite their high sensitivity to ionising radiation HX138 and HX142 do exhibit substantial levels of cellular recovery, suggesting that they may have a significant capacity for repair of radiation-induced lesions.

Cell Survival↗
PubMed1990

The relationship of DNA double-strand break induction to radiosensitivity in human tumour cell lines.

Recent data suggest that the differences in radiosensitivity between cell lines can be related to differences in dsb induction (Radford 1986a). In the light of this we have set out to assess the extent to which differences in radiation survival between human tumour cell lines can be attributed to differences in dsb induction. For nine human tumour lines survival was assayed by clonogenic assay and compared with dsb induction by irradiation at ice-bath temperature as measured by neutral filter elution. The lines varied widely in their sensitivity, ranging from a sensitive neuroblastoma (surviving fraction at 2 Gy, SF2 = 0.13) to a resistant bladder carcinoma (SF2 = 0.62). Dsb induction was found to vary between the cell lines, such that resistant cells generally suffered less damage than sensitive ones. However, the relationship between damage induction and cellular sensitivity was not a simple one, and other factors which may influence sensitivity need to be invoked. These data suggest that, in human tumour cell lines, differences in radiosensitivity may at least in part be due to different levels of damage induction, but that some lines may vary in their tolerance of damage due to differences in biological characteristics such as repair capacity.

Cell Line↗
PubMed1989

Why are some human tumours more radiosensitive than others?

There is now good evidence that the radiosensitivity of human tumour cells varies form one tumour type to another, and that the steepness of the initial part of the cell survival curve correlates with clinical radioresponsiveness. Studies at low dose rate allow differences between tumour cells to be seen more clearly. Current mathematical models of radiation cell killing include two components: a linear (i.e. exponential "alpha-component") and a bending component ("beta-component"). Repair of radiation damage affects only the beta-component. Among the 17 human tumour cell lines that we have studied, the average surviving fraction at 2 Gy due to the alpha-component is 0.44 and that due to the beta-component is 0.88. The beta-effect at 2 Gy appears to be similar in radiosensitive and radioresistant tumours; thus among radiosensitive tumours where the survival due to the alpha-component is below 0.3 the beta-effect makes a very small contribution to overall radiosensitivity in the low-dose region. Steep cell survival curves may appear straight but still be consistent with a modest beta-value. The overall effect of many small fractions will be to amplify the dominance of the alpha-component. The beta-effect is then unimportant because repair will be almost complete. Repair inhibitors may however change this situation, reducing recovery, increasing the beta-effect, and thereby increasing sensitivity. But in the absence of such inhibitors the differences between radiosensitive and radioresistant tumours must be looked for not in repair capacity but in the nature of the alpha-component. The most radiocurable tumours do not have low beta-values; they have higher alpha-values than the less curable tumours.

Cell Line↗
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↗