These signals are assumed to transfer from hit cells to the non-hit cells via gap junctions or culture medium The intercellular signaling can induce DNA damage 23 which may be repaired However, the damage in non-hit cells sometimes persists for a prolonged time 25 , suggesting that the disorder of DNA repair efficiency may have occurred in non-hit cells 26 , 27 , Thus, the damage induction and its repair process in the non-hit cells are presumably different from those in the irradiated cells From the viewpoint of the repair induction system against DNA damage, currently it has been interpreted that an increased radioresistance IRR emerges if the repair capacity overcomes the low-dose HRS in a dose up to 0.
TEs on cell survival considering track structure of radiation were successfully modeled by Hawkins, calling it the microdosimetric-kinetic MK model 31 , 32 , which considers microdosimetry 33 , 34 and sub-lethal damage SLD repair during dose-delivery 32 , 35 , On the contrary, there are several formulations to quantify low-dose HRS and intercellular signaling 30 , 37 , 38 , 39 , 40 , 41 , 42 , However, there is no model analysis considering the kinetics of signal-induced DNA lesions.
Thus, our interest was directed to the development of a biophysical model which can evaluate not only the cell survival in TEs and NTEs but also 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 finally 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. When a cell population is exposed to ionizing radiation, potentially lethal lesions PLLs may be induced along the radiation particle track passing through domains in cells.
Every PLL has a possibility to be repaired. If the number of PLLs in a domain after acute irradiation is proportional to z specific energy and the DNA amount g in the domain 46 , the number of PLLs in the domain as a function of time after irradiation, x d t , is described by. The number of PLLs per domain is given by,. The scenario of non-hit effects in Fig. By solving Eq. Here, g 0 represents DNA amount per domain in kg.
If the irradiation time T [h] is negligibly short in the special case of high-dose-rate irradiation, Eq. Targets that emit the initial signals stimulating substance are regions somewhere in the cell of micron-order size as large as Mitochondria. The number of hits to the region follows a linear-quadratic function of specific energy. Cell-killing signals are increased by signal cascade but are decreased by the decay of the signals and reaction to cells. In the non-hit cells reacted by cell-killing signals, PLLs are induced in proportion to the signal concentration.
Cell death is induced if the LLs remain in the cell nucleus. The conceptual illustration of the scenario that cell-killing signals induce DNA lesions which lead to cell killing is summarized in Fig. In the present model, we assumed that the number of hits to the regions follows a linear-quadratic LQ shape as a function of specific energy. The LQ relation is mathematically useful for considering the hits by a single track and by two tracks Fig. The signal entities are supposed to spread out when the regions are hit 10 , The number of hits N h per domain can be expressed by a linear-quadratic function as.
The number of incident particles which traverse regions in each cell will follow the Poisson statistics because the probability of the traverse in a micro-order area is very low, especially in the case of low-dose exposure. So, the fraction of hit cells is expressed as. A series of cell responses from the signal concentration to DNA damage is summarized here. The PLLs are assumed to be induced in proportion to the amount of cell-killing signals, and the lesions have a potential to be repaired. The average number of the signal-induced PLLs, x b r , t , per non-hit domain nearby hit domains follows the equation.
Here, the average number of PLLs per domain is considered to be a spatially-dependent number. It should be noted that all the signals are released from hit cells that include hit regions. The average number of the PLLs per domain is given by. Thu s , Eq. The modelling of the NTEs takes account of the signal concentration and the number of DNA lesions as a function of time after irradiation.
Taking advantage of this versatility, we next modified the IMK model to express the cell survival after exposure with irradiated cell culture medium ICCM , namely medium transfer bystander effects MTBEs. Then, after the transfer of the ICCM to the dish with the recipient cells, the signal concentration at time t is modified as. Finally, we have a relational expression of the cell surviving fraction with the recipient cell population as. This equation represents the cell survival after exposure with ICCM, by which the probability of hit to regions in NTEs can be analyzed to interpret the underlying mechanism of signal emission quantitatively through the comparison with experimental MTBE data.
We fit Eq. By using these equations for the cell nucleus composed of p domains, we compared the average number of DSB per nucleus estimated by the model with experimental DSB data in primary normal human fibroblasts from the lung, MRC-5 By using these parameters, we illustrated cell survival curves in comparison with the experimental survival data for the VA 56 , 57 , 58 , 59 , 60 , 61 and TD cell lines 62 , 63 , 64 , Whilst the data in MTBEs was used to evaluate the linear-quadratic relation of target activation to release signals, a set of SF data in CHO-K1 cells was used to investigate the relation between the low-dose HRS and the inactivation of the repair in non-hit cells.
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To check the fit quality of the IMK model to the experimental data of signals, DNA damage kinetics and cell survival, we calculated the R 2 value given by. The chi-square and AIC values are defined by. According to Hu et al. Since the damage induction in the NTEs may have occurred at an earlier time after irradiation, we next 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.
The black lines and symbols in Fig. The number in Fig. The curves by the IMK model in consideration of inactivation of the repair in non-hit cells agree well with the experimental data. In Fig. Under the assumption that the repair in non-hit cells is inactivated, the IMK model reproduced the time dependency of DNA-DSBs in good agreement with experimental data The symbols represent the experimental SF data reported by Marples et al.
The black solid line and dotted line represent the curve described by the IMK model with or without NTEs, respectively. The IC in Fig. The symbols represent the experimental SF data 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , As shown in Fig. The agreement between the resultant curves and the experimental data is also fair.
Comparison between the modified IMK model Eq. The figures show the relation between the surviving fraction of recipient cells affected by the ICCM and absorbed dose in the irradiated donor cell population: A for HPV-G cell line and B for E48 cell line, respectively. It is noted that the quadratic term in Eq. In the present model, the DNA repair function in non-hit cells is newly introduced as an inactivation factor.
Here, we assumed that a and b d are cell-specific parameters in the IMK model. In the course of the model analysis about DNA repair efficiency of non-hit cells c b , it is suggested that the repair in non-hit cells is almost inactivated. The result in Fig. Comparison between the surviving fraction in our model and the experimental data for non-treated CHO-K1 cells and repair-inhibited cells The number of hits to targets to release signals in NTEs and the signal amount have been thought to be related with the mechanism as a function of absorbed dose in Gy or specific energy 11 , In the present model, we defined a formula for the mechanism as a LQ relation.
To evaluate this definition, we further compared the IMK model with the previous model linear relation reported by Liu et al. The sets of parameters by Liu et al. In addition, we fitted the previous model by Friedland et al. Although the model including a lot of parameters by Friedland et al. It is generally accepted that the LQ relation in hit number depends on the number of radiation particles in the LQ model This suggests that the parameters in NTEs are cell-specific.
This value may also depend on the cell type. Fernandez-Palomo et al. Some previous investigations indicate that the defect of DNA repair in non-irradiated cells is related to the bystander effect 27 , According to the report by Rothkamm et al. Thus, it is reasonable to suppose that the DNA repair function in non-irradiated cells is inactivated.
Original Research ARTICLE
From the viewpoint of the repair capability in a cell population, it has been interpreted as that the increased radioresistance IRR is associated with overcoming low-dose HRS As is shown in Fig. This suggests that the inactivation of DNA repair in non-hit cells tends to enhance cell-killing or to decrease radioresistance after a low-dose irradiation.
As to the increase of repair by virtue of the repair function, evidence have been reported 75 , In this study, through the analyses using the developed IMK model, we have demonstrated NTEs by the combination of a variety of processes: signal transfer from hit cells, kinetics of DSBs to enhance cell killing and disorder of the DNA repair function, to show characteristics of the radiosensitivity of cells in conformity with experimental evidences.
In this study, an integrated microdosimetric-kinetic IMK model taking account of NTEs was applied to demonstrate the experimental data of the cell-killing signals, number of DSBs per nucleus and cell survival. From the comparison of the results by the model with experimental data, it was shown: i a LQ relation to express the hit probability for emitting signals is suitable to describe cell killing in NTEs, ii low-dose hyper-radiosensitivity HRS is attributed to the combination of the induction of DSBs by the signals and low DNA repair efficiency in non-hit cells, and iii the low-dose HRS is enhanced more as the DNA repair efficiency in non-hit cells is lower.
- 1. Introduction!
- DNA repair.
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Hall, E. Cell survival curves. In: Hall, E. Radiobiology for the Radiologist. Nagasawa, H. Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect.
Intra-and Intermolecular Interactions, Radiation Effects in DNA Cells, and Repair Mechanisms
Morgan, W. Non-targeted bystander effects induced by ionizing radiation. Wouters, B. Irradiation-induced damage and the DNA damage response.
Related Intra- and Intermolecular Interactions, Radiation Effects in DNA Cells, and Repair Mechanisms
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