Characterization of in vitro radiosensitization in mammalian cells using biomathematical modelling: implications for hypofractionated radiotherapy with a combined modality approach

Objective: It is unclear whether radiosensitization is beneficial when radiotherapy is administered at a high dose per fraction. The aim of this study was to assess the impact of radiation dose on the effectiveness of a broad range of radiosensitizers. Methods: We analyzed 653 pairs of clonogenic survival curves in 285 published articles, in which modifications of radiosensitivity were studied using the colony-forming assay. The modifications of radiosensitivity were arbitrarily classified into 20 classes. The survival curves were fitted to two biomathematical models: the linear-quadratic model and the repair-misrepair (RMR) model. Results: We found that radiosensitization was predominantly characterized by an increase of the alpha value (alpha-sensitization) without an increase of the beta value (beta-sensitization). A subset analysis revealed that all 20 classes showed significant alpha-sensitization. In contrast, only oxygen/hypoxic sensitizers (oxygen) and poly(adenosine diphosphate-ribose) polymerase inhibition (PARPi) exhibited beta-sensitization. An analysis using the RMR model revealed two major sources of radiosensitization: an increased residual DNA lesion through repair inhibition and a shift from linear repairs to quadratic misrepairs, leading to enhanced lethal chromosomal aberrations. Conclusion: Oxygen and PARPi were found to show beta-sensitization, which was favourable for eliciting a comparable degree of sensitization in the higher dose range. Reduced fidelity of the repair was suggested to be a possible mechanism of beta-sensitization. Further study targeting beta-sensitization is needed to develop a novel combined modality therapy with high-dose-per-fraction radiotherapy. Advances in knowledge: Radiosensitization can be classified into two groups, alpha- and beta-sensitizations. These two phenomena may stem from distinct underlying mechanisms.