Application of the Linear-Quadratic model to targeted radionuclide therapy

Abstract

PhDThe principal aim of this work was to test the hypothesis that the Linear-Quadratic (LQ) model of cell survival, developed for external beam radiotherapy (EBRT), could be extended to targeted radionuclide therapy (TRT) in order to predict dose-response relationships. The secondary aim was to establish the relevance of particular radiobiological phenomena to TRT and relate these results to any deviations from the response predicted by the LQ Model. Methods: Cancer cell lines were treated with either EBRT or an in-vitro model of TRT. Dosimetry for the TRT was calculated using radiation transport simulations with the Monte Carlo PENELOPE code. Clonogenic as well as functional biological assays were used to assess cell response. Results: Accurate dosimetry for in-vitro exposures of cell cultures to radioactivity was established. LQ parameters of cell survival were established for cancer cell lines reported to be prone to apoptosis, low dose hypersensitivity (LDH) or the bystander effect. For apoptotic cells and cells exhibiting a bystander effect in response to EBRT, LQ parameters were found to be predictive of cell response to TRT. Apoptosis was not found to be a mode of cell death more specific to TRT than to EBRT. Bystander effects could not be demonstrated in cells exposed to TRT. Exposure to low doses of radiation may even protect against the bystander effect. The LQ model was not predictive of cell response in cells previously shown to exhibit LDH. This led to a development of the LQ model based upon a threshold dose-rate for maximum repair. However, the current explanation of LDH may not explain the inverse dose-rate response. Conclusion: The LQ model of cell survival to radiation has been shown to be largely predictive of response to low dose-rate irradiation. However, in cells displaying LDH, further adaptation of the model was require