Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects

Abstract

In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area of a T25 flask containing the cells (half-field) or 100% of the flask (uniform-field). We also modelled the impact of dose-rate effects and intercellular signalling on cell-killing. Applying the model to the survival data, it is found that (i) in-field cell survival under half-field exposure is higher than uniform-field exposure for the same delivered dose; (ii) the importance of sub-lethal damage repair (SLDR) in AGO1522 cells is reduced under half-field exposure; (iii) the yield of initial DNA lesions measured with half-field exposure is smaller than that with uniform-field exposure. These results suggest that increased cell survival under half-field exposure is predominantly attributed not to rescue effects (increased SLDR) but protective effects (reduced induction of initial DNA lesions). In support of these protective effects, the reduced DNA damage leads to modulation of cell-cycle dynamics, i.e., less G 1 arrest 6 h after irradiation. These findings provide a new understanding of the impact of dose-rate effects and protective effects measured after modulated field irradiation.

A theoretical cell-killing model to evaluate oxygen enhancement ratios at DNA damage and cell survival endpoints in radiation therapy

“…34 It has been tested and the factor can reproduce experimental cell survival data. 31,32,34,35 Further,…”

“…The integrated cell-killing model used in this study, so-called "integrated microdosimetric-kinetic (IMK) model", [30][31][32][33] is composed of targeted effects and non-targeted effects. The inclusion of the effects has been tested by comparing the outcomes with in vitro experimental survival data.…”

“…In these regards, to consider the progression of oxygen effects, a more biologically detailed model based on DNA damage yield than the conventional LQ model 13 is necessary. When compared to many available models for hypoxia, 10,11,28,29 the integrated microdosimetric-kinetic (IMK) model [30][31][32][33] has unique features such as involvement of DNA damage kinetics 34,35 and the cell-cycle phase. 31 The model is suitable for estimating radio-sensitivity under chronic lower oxygen pressure.…”

4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication

“…In these circumstances, we thought that a theoretical model prediction of cell-killing in combination with the cell experiments can be a powerful approach to interpret the biological data 26 – 31 . Specifically, we are interested in modelling the pharmacological effects by 4-MU treatment and investigating quantitatively the radiosensitizing mechanisms by the use of an integrated cell-killing model considering several biological responses (i.e., DNA damage repair kinetics and intercellular communication) 32 , 33 . This approach must be of great importance as translational study between radiation biology and pre-clinical evaluation in the field of radiotherapy 31 , 34 .…”

4-Methylumbelliferone Administration Enhances Radiosensitivity of Human Fibrosarcoma by Intercellular Communication

“…[26][27][28][29][30][31] Specifically, we are interested in modelling the pharmacological effects by 4-MU treatment and investigating quantitatively the radiosensitizing mechanisms by the use of an integrated cell-killing model considering several biological responses (i.e., DNA damage repair kinetics and intercellular communication). 32,33 This approach must be of great importance as translational study between radiation biology and pre-clinical evaluation in the field of radiotherapy. 34,35 In this study, we performed the cell experiments (clonogenic survival assay and ROS detection assay) and the model analysis for predicting tumour cell survival.…”