The response of tissues to very low doses per fraction: a reflection of induced repair?
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Animals↗
Biomedical subjects
B Marples
Publications and source records attributed to B Marples.
Hypersensitivity of a human tumour cell line to very low radiation doses.
Survival of HT29 cells was measured after irradiation with single doses of X-rays (0.05-5 Gy) and neutrons (0.025-1.5 Gy), using a Dynamic Microscopic Imaging Processing Scanner (DMIPS) with which individual cells can be accurately located in tissue culture flasks, their positions recorded, and after an appropriate incubation time the recorded positions revisited to allow the scoring of survivors. The response over the X-ray dose range 2-5 Gy showed a good fit to a Linear-Quadratic (LQ) model. For X-ray doses below 1 Gy, an increased X-ray effectiveness was observed with cell survival below the high-dose LQ prediction. The value of --dose/loge (SF) for each experimental data point, plotted against dose, demonstrated clearly how X-rays are maximally effective at doses approaching zero, becoming less effective as the dose increases and with minimal effectiveness at about 0.6 Gy then becoming more effective again as the dose increases above 1.5 Gy. This phenomenon was not seen with neutrons. Neutron RBE was calculated for each X-ray data point by taking each X-ray survival value and comparing it with the common LQ fit to all the neutron data. Over the X-ray dose range 0.05-0.2 Gy, the RBE is close to 1 indicating that these very low doses of X-rays are of similar effectiveness to neutrons in killing cells. The increase in RBE with increasing dose over the range 0.05-1 Gy, and the slight decrease in RBE above 1 Gy, reflect primarily the changes in X-ray sensitivity over the whole dose range of 0.05-5 Gy. Several arguments suggest that this phenomenon could reflect an induced radioresistance so that in this system low single doses of X-rays are more effective per Gy than higher doses in reducing cell survival because only at higher doses, above a threshold, is there sufficient damage to trigger radioprotective mechanisms.
Cell Survival↗
The response of Chinese hamster V79 cells to low radiation doses: evidence of enhanced sensitivity of the whole cell population.
High-resolution measurements of the survival of asynchronous Chinese hamster V79-379A cells in vitro after single doses of X rays (0.01-10.0 Gy) and neutrons (0.02-3.0 Gy) were made using a computerized microscope for locating and identifying cells (Palcic and Jaggi, Int. J. Radiat. Biol. 50, 345-352, 1986). The X-ray response from 1 to 10 Gy showed a good fit to a linear-quadratic (LQ) dose-survival model, but with X-ray doses below 0.6 Gy, an increased X-ray effectiveness was observed, with cell survival below the prediction made from the data above 1 Gy using the LQ model. The effect per unit dose (-log(e)SF/dose) increased by a factor of approximately 2, from 0.19 Gy-1 at a dose of 1 Gy to 0.37 Gy-1 at a dose of 0.1 Gy. This phenomenon was not seen with neutrons, and cell survival decreased exponentially over the whole neutron dose range studied. Further data suggest that this phenomenon is unlikely to be due to a subpopulation of X-ray-sensitive cells determined either genetically or phenotypically by distribution of the population within the cell cycle. The existence of low-dose sensitivity also appeared to be independent of dose rate in the range 0.016-1.7 Gy min-1. A possible explanation of these results is that the phenomenon reflects "induced repair" or a stress response: low doses in vitro (or low doses per fraction in vivo) are more effective per gray than higher doses because only at the higher doses is there sufficient damage to trigger repair systems or other radioprotective mechanisms.
Animals↗
Does induced repair determine the lethal effects of very low radiation doses?
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Animals↗
Adaptive response and induced resistance.
Cellular stress responses are upregulated following exposure to radiation and other DNA-damaging agents. Therefore radiation response can be dose dependent so that small acute exposures (and possibly exposures at very low dose rates?) are more lethal per unit dose than larger exposures above a threshold (typically 10-40 cGy) where induced radioprotection is triggered. We have termed these interlinked phenomena low-dose hypersensitivity (HRS) and induced radioresistance (IRR) as the dose increases. HRS/IRR has been recorded in cell-survival studies with yeast, bacteria, protozoa, algae, higher plant cells, insect cells, mammalian and human cells in vitro, and in studies on animal normal-tissue models in vivo. There is indirect evidence that cell survival-related HRS/IRR in response to single doses is a manifestation of the same underlying mechanism that determines the well-known adaptive response in the two-dose case and that it can be triggered by high- and low-LET radiations as well as a variety of other stress-inducing agents such as hydrogen peroxide and chemotherapeutic agents. Little is currently known about the precise nature of this underlying mechanism, but there is evidence that it operates by increasing the amount and rate of DNA repair, rather than by indirect mechanisms such as modulation of cell-cycle progression or apoptosis. Changed expression of some genes, only in response to low and not high doses, may occur within a few hours of irradiation and this would be rapid enough to explain the phenomenon of induced radioresistance although its specific molecular components have yet to be identified. Net cancer risk is a balance between cell transformation and cell kill. Our known low-dose cell-survival responses suggest that lethality may more than compensate for transformation at low radiation doses. However, adaptive reduction in sensitivity to radio-mutation has also been reported, which implies the existence also of enhanced mutation following very low single doses. So far this has not been confirmed, but provided the trigger dose for mutational protection was lower than the trigger dose for protection against cytotoxicity, cell killing would still dominate over at least the first 10 cGy of low-LET exposure. This would lead to a non-linear, threshold, dose-risk relationship and even provide some explanation for anecdotal reports of apparent 'health promoting' effects and lowered cancer risk from very low exposure to ionising radiation.
Adaptation, Physiological↗
Is low-dose hyper-radiosensitivity a measure of G2-phase cell radiosensitivity?
Low-dose hyper-radiosensitivity describes a phenomenon by which cells die from excessive sensitivity to small single doses of ionizing radiation below approximately 20-30 cGy. This review describes experimental data that strongly imply that low-dose hyper-radiosensitivity is exclusively associated with the survival response of cells in the G2 phase of the cycle. This G2-centric concept arose when the characteristic cell survival pattern that denotes low-dose hyper-radiosensitivity was not detected in the radiation survival response of cell populations enriched in G1 or S phase cells. In contrast, an extended or exaggerated low-dose hyper-radiosensitivity response was evident from populations selected to contain only G2 phase cells by flow cytometry cell sorting. The historical data that has defined the field of low-dose hyper-radiosensitivity will be considered with respect to the radiation sensitivity of, and cell cycle checkpoints specific to, G2 phase cells. A working model of the putative mechanism of low-dose hyper-radiosensitivity will be presented within this context. The foundation of the model is a rapidly occurring dose-dependent pre-mitotic cell-cycle checkpoint that is specific to cells irradiated in the G2 phase. This early G2 phase checkpoint has been demonstrated to exhibit a dose expression profile that is comparable to the cell-survival pattern that defines low-dose hyper-radiosensitivity and is therefore a likely key regulator of the phenomenon.
Animals↗