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 G1 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.
Highlights
Materials and MethodsIn this model, reparable lesions (potentially lethal lesion: probability between sub-lesions (PLLs)) are assumed to be DNA lesions with cell toxicity, which may transform into non-reparable lesions (lethal lesions: LLs) or be completely repaired[28]
Www.nature.com/scientificreports there are several reports about signal-induced radio-resistance[21,22,23], which can sometimes be observed in cells in-field under half-field irradiation in comparison with a uniform field exposure[12,13]
The survivals for the cases of τ = 0 and ∞ (S(0) and S(∞)) and the initial slop of dS/dτ for in-field cells under uniform-field (AIF = 1.0) (Fig. 2AI,BI) and in-field cells under half-field (AIF = 0.5) (Fig. 2AII,BII) were used for determining the (a + c) and the β0 values based on Eqs (7) and (8)
Summary
In this model, reparable lesions (potentially lethal lesion: PLL) are assumed to be DNA lesions with cell toxicity, which may transform into non-reparable lesions (lethal lesions: LLs) or be completely repaired[28]. Based on previous modelling[10,35], the cell surviving fraction for DNA-TEs ST can be given by:. In the model for DNA-targeted effects, (a + c) and β0 can be obtained from a split dose cell recovery curve, whilst α0 can be determined by fitting to the acute exposure cell survival curve. (ii) The probability of a given cell having an activated target for emitting NTE signals fh(D) follows Poisson statistics with the number of activated targets for NTEs, giving fh(D) = 1−e−[(αb+γβb)D+βbD2]34, where D denotes cumulative absorbed dose. According to previous reports of the MK model[30], the formula to calculate the (a + c) value, that is approximately equivalent to SLDR, is given by c) lim τ→0
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