scholarly journals A Mechanistic DNA Repair and Survival Model (Medras): Applications to Intrinsic Radiosensitivity, Relative Biological Effectiveness and Dose-Rate

2021 ◽  
Vol 11 ◽  
Author(s):  
Stephen Joseph McMahon ◽  
Kevin M. Prise

Variations in the intrinsic radiosensitivity of different cells to ionizing radiation is now widely believed to be a significant driver in differences in response to radiotherapy. While the mechanisms of radiosensitivity have been extensively studied in the laboratory, there are a lack of models which integrate this knowledge into a predictive framework. This paper presents an overview of the Medras model, which has been developed to provide a mechanistic framework in which different radiation responses can be modelled and individual responses predicted. This model simulates the repair of radiation-induced DNA damage, incorporating the overall kinetics of repair and its fidelity, to predict a range of biological endpoints including residual DNA damage, mutation, chromosome aberration, and cell death. Validation of this model against a range of exposure types is presented, including considerations of varying radiation qualities and dose-rates. This approach has the potential to inform new tools to deliver mechanistic predictions of radiation sensitivity, and support future developments in treatment personalization.

Mutagenesis ◽  
2014 ◽  
Vol 29 (4) ◽  
pp. 279-287 ◽  
Author(s):  
Kristina Taylor ◽  
Jennifer A. Lemon ◽  
Douglas R. Boreham

2021 ◽  
Author(s):  
Elena K. Zaharieva ◽  
Megumi Sasatani ◽  
Kenji Kamiya

We present time and dose dependencies for the formation of 53BP1 and γH2AX DNA damage repair foci after chronic radiation exposure at dose rates of 140, 250 and 450 mGy/day from 3 to 96 h, in human and mouse repair proficient and ATM or DNA-PK deficient repair compromised cell models. We describe the time/dose-response curves using a mathematical equation which contains a linear component for the induction of DNA damage repair foci after irradiation, and an exponential component for their resolution. We show that under conditions of chronic irradiation at low and medium dose rates, the processes of DNA double-strand breaks (DSBs) induction and repair establish an equilibrium, which in repair proficient cells manifests as a plateau-shaped dose-response where the plateau is reached within the first 24 h postirradiation, and its height is proportionate to the radiation dose rate. In contrast, in repair compromised cells, where the rate of repair may be exceeded by the DSB induction rate, DNA damage accumulates with time of exposure and total absorbed dose. In addition, we discuss the biological meaning of the observed dependencies by presenting the frequency of micronuclei formation under the same irradiation conditions as a marker of radiation-induced genomic instability. We believe that the data and analysis presented here shed light on the kinetics of DNA repair under chronic radiation and are useful for future studies in the low-to-medium dose rate range.


2019 ◽  
Vol 18 ◽  
pp. 153303381987130
Author(s):  
Francois Chevalier ◽  
Dounia Houria Hamdi ◽  
Charlotte Lepleux ◽  
Mihaela Temelie ◽  
Anaïs Nicol ◽  
...  

Chondrosarcomas are malignant tumors of the cartilage that are chemoresistant and radioresistant to X-rays. This restricts the treatment options essential to surgery. In this study, we investigated the sensitivity of chondrosarcoma to X-rays and C-ions in vitro. The sensitivity of 4 chondrosarcoma cell lines (SW1353, CH2879, OUMS27, and L835) was determined by clonogenic survival assays and cell cycle progression. In addition, biomarkers of DNA damage responses were analyzed in the SW1353 cell line. Chondrosarcoma cells showed a heterogeneous sensitivity toward irradiation. Chondrosarcoma cell lines were more sensitive to C-ions exposure compared to X-rays. Using D10 values, the relative biological effectiveness of C-ions was higher (relative biological effectiveness = 5.5) with cells resistant to X-rays (CH2879) and lower (relative biological effectiveness = 3.7) with sensitive cells (L835). C-ions induced more G2 phase blockage and micronuclei in SW1353 cells as compared to X-rays with the same doses. Persistent unrepaired DNA damage was also higher following C-ions irradiation. These results indicate that chondrosarcoma cell lines displayed a heterogeneous response to conventional radiation treatment; however, treatment with C-ions irradiation was more efficient in killing chondrosarcoma cells, compared to X-rays.


RSC Advances ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 6845-6858 ◽  
Author(s):  
N. T. Henthorn ◽  
J. W. Warmenhoven ◽  
M. Sotiropoulos ◽  
A. H. Aitkenhead ◽  
E. A. K. Smith ◽  
...  

Relative Biological Effectiveness (RBE) is a controversial and important topic in proton therapy. This work uses Monte Carlo simulations of DNA damage for protons and photons to probe this phenomenon, providing a plausible mechanistic understanding.


2015 ◽  
Vol 42 (6Part20) ◽  
pp. 3461-3462 ◽  
Author(s):  
D Mirkovic ◽  
C Peeler ◽  
D Grosshans ◽  
U Titt ◽  
R Taleei ◽  
...  

2015 ◽  
Vol 54 (9) ◽  
pp. 1623-1630 ◽  
Author(s):  
Brita S. Sørensen ◽  
Michael R. Horsman ◽  
Jan Alsner ◽  
Jens Overgaard ◽  
Marco Durante ◽  
...  

2022 ◽  
Vol 23 (2) ◽  
pp. 878
Author(s):  
Laura C. Paterson ◽  
Amy Festarini ◽  
Marilyne Stuart ◽  
Fawaz Ali ◽  
Christie Costello ◽  
...  

Theoretical evaluations indicate the radiation weighting factor for thermal neutrons differs from the current International Commission on Radiological Protection (ICRP) recommended value of 2.5, which has radiation protection implications for high-energy radiotherapy, inside spacecraft, on the lunar or Martian surface, and in nuclear reactor workplaces. We examined the relative biological effectiveness (RBE) of DNA damage generated by thermal neutrons compared to gamma radiation. Whole blood was irradiated by 64 meV thermal neutrons from the National Research Universal reactor. DNA damage and erroneous DNA double-strand break repair was evaluated by dicentric chromosome assay (DCA) and cytokinesis-block micronucleus (CBMN) assay with low doses ranging 6–85 mGy. Linear dose responses were observed. Significant DNA aberration clustering was found indicative of high ionizing density radiation. When the dose contribution of both the 14N(n,p)14C and 1H(n,γ)2H capture reactions were considered, the DCA and the CBMN assays generated similar maximum RBE values of 11.3 ± 1.6 and 9.0 ± 1.1, respectively. Consequently, thermal neutron RBE is approximately four times higher than the current ICRP radiation weighting factor value of 2.5. This lends support to bimodal peaks in the quality factor for RBE neutron energy response, underlining the importance of radiological protection against thermal neutron exposures.


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