Mechanisms and implications of the low dose intrinsic radiation survival response
Creators: name: Wouters, Bradly Garry
Publisher: name: University of British Columbia
Year: 2009

description: Previous studies in this laboratory using a precise assay for measurement of cell survival revealed substructure in the radiation response of asynchronously growing cells. The substructure appeared to result from selective killing of sensitive cells in the cellcycle, such that the radiosensitivity of the surviving population decreased with increasing dose. Accurate characterization of the low dose response with the linear quadratic (LQ) model resulted in smaller α/β ratios than predicted from a fit to the entire response, suggesting that survival at low doses must be measured, rather than extrapolated, in order to evaluate particular treatment strategies. We have used this same assay in an in vitro model system, based on a panel of several human tumour cell lines, to investigate the efficacy of two hypoxic radiosensitizers, etanidazole (2-(2-nitro-l-imidazolyl)-N-(2- hydroxyethyl) acetamide) and RB6145 (lH-imidazole-l-ethanol, α-([(2-bromoethyl) amino]methyl) -2-nitro-,monohydrobromide). The results reveal a cell line and radiation dose dependence for the sensitizing ability of these drugs. Modeling the low dose data indicates that sensitization by RB6145 and etanidazole results primarily from modification of the α and β parameters, respectively. Consequently, the efficacy and dose dependence of these sensitizers are tumour specific, determined more by differences in the low dose α and β values than by overall radiosensitivity. In order to understand the variability of radiosensitivity and α/β ratios among different cell lines, the radiation dose-response relationship was investigated at very low doses (-0-4 Gy) in 3 human tumour cell lines. The results indicate a region of hypersensitivity below doses of -0.5 Gy. This is followed by an increase in resistance from -0.3 to 0.7 Gy, beyond which the response follows that predicted by the LQ model. Modeling the radiation responses, and survival measurements in synchronous populations, suggest it is unlikely that this phenomenon is due to a small sub-population of sensitive cells (e.g., mitotic), but rather that it reflects the ability of the cells to initiate a radiation resistance mechanism. The results also suggest a lack of sub-lethal damage repair following doses within the hypersensitive region. Together, these results suggest that a dose-dependent alteration in the processing of DNA damage at low doses may contribute to intrinsic radiosensitivity. The implications of the low dose response were also evident in measurements of the relative biological effectiveness (RBE) of the 70 MeV proton spread out Bragg peak (SOBP) at TRIUMF. V79-WNRE Chinese hamster cell survival responses were measured as a function of dose and depth within the SOBP and compared with the response to ⁶⁰Co γ-rays. The shapes of the low dose responses (α/β ratios) following proton and ⁶⁰Co irradiation exhibited significant differences which impacted on the absolute value and dose dependence of the RBE. Above doses of 5 Gy, the RBE throughout the SOBP was relatively constant (1.21 ±0.05), but below 4 Gy it increased significantly with decreasing dose. Based on the results with radiosensitizers, we argue that the RBE value and its dose dependence will be cell line dependent, and should be predicted, in part, by the low dose a and (3 values determined from the X-ray or ⁶⁰Co response. A consistent increase in RBE with increased depth in the SOBP was also observed, and at the distal edge of the stopping distribution it increased to an extent that may be of concern when this region of the treatment volume is close to sensitive tissues. These results illustrate the oversimplification of the use single RBE values for irradiation protocols, and argues for the use of proton gray doses rather than cobalt-equivalent grays.