Mayes, Catherine Ruth; (2001) Effects of low dose-rate irradiation on human tumour cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The phenomenon of hyper-radiosensitivity (HRS) to very low doses of radiation has been observed in many tumour cell lines. HRS is a decrease in cell survival at low acute doses (<1 Gy) below the prediction by the Linear-Quadratic model for the response to higher doses. This increased sensitivity to low doses is surmised to be due to a failure to activate "repair processes". This thesis explores a corresponding enhanced sensitivity that occurs after clinically-relevant low dose-rate exposures. Two novel low dose-rate irradiation systems were developed: (1) an 125I irradiator containing nine 125 I brachytherapy seeds was used to irradiate cells at dose rates from 3 to 40cGy h-1; (2) a 60Co y-source and an attenuating water tank were used to carry out simultaneous irradiations over a wide range of dose rates (1 to 100 cGy h-1). Three asynchronously growing human tumour cell lines (PC3, T98G, A7), which demonstrated HRS to acute single doses, were irradiated with low dose-rate 60Co y-rays. These cell lines showed a strong inverse dose-rate effect on cell survival at dose rates below l00cGy h-1, Analysis of the cell cycle using propidium iodide staining indicated that this inverse dose-rate effect was not due to pre-mitotic accumulation or other cell-cycle perturbations. T98G cells can be put into a reversible G1 arrest upon reaching confluence. Confluent T98G cells also show an inverse dose-rate effect at low dose rates (5 and l0cGy h-1) and a sparing effect at higher dose rates (30 and 60cGy h-1). The HRS-negative cell line investigated, U373MG, did not demonstrate an inverse dose-rate effect. Experiments were carried out to determine combinations of dose and dose rate that enhanced survival. T98G cells were irradiated at low-dose rate and then at acute doses to determine the presence of HRS with varying time intervals. Asynchronous T98G cells showed HRS when previously irradiated with dose rates ranging from 5 to 60cGy h-1 to total doses of 2 and 5 Gy, suggesting repair mechanisms are not switched on during the LDR irradiation. In confluent cells irradiated at dose rates of 60 and 30cGy h-1 to a total dose of 5 Gy and then immediately with acute-dose X-rays, no HRS was seen. However, HRS was observed if an interval of 4 h was left between irradiations. HRS was present at dose rates of 60 and 30 cGy h-1 at a total dose of 2 Gy with both a 0 h and 4 h interval between irradiations, suggesting that at 30 and 60cGy h-1 repair is triggered between a total dose of 2 and 5 Gy. These data indicate that the inverse dose-rate effect and HRS may be mechanistically related and this effect may contribute to the clinical efficacy of 125I brachytherapy.

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