Integrated Modelling of Cell Responses after Irradiation for DNA-Targeted Effects and Non-Targeted Effects

Yusuke Matsuya,Hiroyuki Date,Go Okuyama,Yuji Yoshii,Kohei Sasaki

doi:10.1038/s41598-018-23202-y

Abstract

Intercellular communication after ionizing radiation exposure, so-called non-targeted effects (NTEs), reduces cell survival. Here we describe an integrated cell-killing model considering NTEs and DNA damage along radiation particle tracks, known as DNA-targeted effects (TEs) based on repair kinetics of DNA damage. The proposed model was applied to a series of experimental data, i.e., signal concentration, DNA damage kinetics, cell survival curve and medium transfer bystander effects (MTBEs). To reproduce the experimental data, the model considers the following assumptions: (i) the linear-quadratic (LQ) function as absorbed dose to express the hit probability to emit cell-killing signals, (ii) the potentially repair of DNA lesions induced by NTEs, and (iii) lower efficiency of repair for the damage in NTEs than that in TEs. By comparing the model results with experimental data, we found that signal-induced DNA damage and lower repair efficiency in non-hit cells are responsible for NTE-related repair kinetics of DNA damage, cell survival curve with low-dose hyper-radiosensitivity (HRS) and MTBEs. From the standpoint of modelling, the integrated cell-killing model with the LQ relation and a different repair function for NTEs provide a reasonable signal-emission probability and a new estimation of low-dose HRS linked to DNA repair efficiency.

Highlights

The damage induction and its repair process in the non-hit cells are presumably different from those in the irradiated cells[29]
A potentially lethal lesions (PLLs) is assumed to undergo one of three transformations: (i) a PLL transforms into a LL via a first-order process at a constant rate a [h−1]; (ii) two PLLs interact with each other and transform into a LL via a second-order process at a constant rate bd [h−1]; (iii) a PLL is repaired by a DNA repair function via a first-order process at constant rate c [h−1]
Since the damage induction in the non-targeted effects (NTEs) may have occurred at an earlier time after irradiation, we tried to reproduce the kinetics of the number of DSBs per nucleus induced by NTEs, assuming that the first messenger of calcium induces the damage

Summary

Introduction

The damage induction and its repair process in the non-hit cells are presumably different from those in the irradiated cells[29]. Our interest was directed to the development of a biophysical model which can evaluate the cell survival in TEs and NTEs and damage kinetics associated with DNA repair in non-hit cells. To our knowledge, this is the first model estimation for a relation between shape of low-dose HRS and DNA repair function in non-hit cells. By applying the model to reference data of intercellular signals, DNA damage kinetics and surviving fraction after irradiation, our model estimation shows that the degree of repair efficiency in non-hit cells is a main factor responsible for modifying low-dose HRS in cell survival curves. The number of LLs per domain, wd, can be expressed by the equation, d dt wd axd(t)

Results

Discussion

Conclusion