Abstract
Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R2 > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity.
Highlights
Whilst it is widely acknowledged that this is only an approximation of the true behaviour of the system and considerable debate exists about its wider applicability[2], this characterisation represents a useful surrogate for tumour control and normal tissue complication and broadly captures the sensitivity of tumours at a population level
We develop a model which implements high-level characterisations of DNA repair through different pathways, cell cycle effects, and cell death processes to provide a mechanistically defined model of cellular responses to ionising radiation
These papers were selected as they represent systematic studies of cell lines with similar origins with known mutations in individual genes in key DNA repair pathways
Summary
Whilst it is widely acknowledged that this is only an approximation of the true behaviour of the system and considerable debate exists about its wider applicability[2], this characterisation represents a useful surrogate for tumour control and normal tissue complication and broadly captures the sensitivity of tumours at a population level. The integration of genetic heterogeneity to provide personalised radiotherapy dose prescriptions could significantly improve treatment outcomes and offer a more rationally informed balance between tumour control and normal tissue toxicity This seems attractive given that many of the genetic determinants of radiation response are well understood–processes such as DNA repair and cell-cycle arrest have been extensively studied, both directly with radiation as well as in the wider field of molecular biology. The linear-quadratic model is poorly suited to understanding these factors, as its empirical parameters are only indirectly linked to the mechanistic drivers of radiation response, making it difficult to predict quantitatively the impact of a given mutation This is true when multiple genes are mutated, as occurs commonly in cancer. Numerous models have been developed of individual pathways such as DNA repair, chromosome aberration formation, apoptosis or intercellular signalling[17,18,19,20]
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