Modelling Of Cellular Survival Following Radiation-induced DNA Damage

With the concept of precision medicine being proposed,more and more hospitals are planning to introduce advanced radiotherapy techniques which make use of protons and carbon ions recently.As compared to photons,ion beams are found to be not only better dose distribution physically,but also more effective biologically if the same absorbed dose is applied.In order to assess the biological effectiveness of ion beam more accurately,two problems have been discussed in this dissertation: one is how to simulate the yield and distribution of DNA damage as well as different types of chromosome aberrations caused by ionizing radiation with different beam quality,which is commonly characterized by the linear energy transfer(LET);the other is how to establish cell survival mechanism models based on radiation-induced DNA damage.Main work of this dissertation is as follows:(1)The DNA damage module and DNA damage repair module of nanodosimetry biophysical Monte Carlo simulation code(NASIC),which is only suitable to photons and electrons,has been optimized in this dissertation,so that it is suitable for more radiation types such as protons and heavy ions,and more functions have been added to NASIC.For the DNA damage module,the statistics of DNA fragment length have been provided.By comparing the outputs of the DNA damage module with the experimental data on the measurements of the length of DNA fragment,the underestimation of the DSB yield in the measurements has been found.In the DNA damage repair module,the statistics of more types of chromosome aberrations have been provided,and the locations of the nuclear matrix attachment,the length of the unrecombinatable DNA fragment and the parameters on state changing of the DSB end have been reselected,which makes the dose-response relationship of simulated chromosome aberration induced by photons being linear quadratic,as well as the DNA damage repair module being suitable to more radiation types.(2)According to mechanism of radiation-induced DNA damage and DNA damage repair,as well as the detailed information of radiation-induced DNA damage and chromosome aberration simulated by NASIC,the relationship among radiation-induced DNA damage,DNA damage repair and cell death has been analyzed,and the cell survival models based on DNA double strand break,DNA fragment distribution and chromosome aberration have been proposed respectively.The propose models have been validated by experimental data of cell survival.It shows that the models avoid the underestimation of cell surviving fraction at high dose range with the linear-quadratic(LQ)model.The benefit is that the models with the parameters for the same kind of cells are suitable to different types of particles with different energy.(3)In the molecular and cellular level,the meanings of the biological parameters,? and ? have been discussed,the reasons for the underestimation of cell surviving fraction at high dose range with the LQ model have been analyzed,and the effect of clustered DNA damage and the over killing effect have been described quantitatively according to the cell survival models proposed in this dissertation,which could be useful as reference for the clinic of particle therapy.In conclusion,on the one hand,the work in this dissertation has made the nanodosimetry biophysical Monte Carlo simulation code,NASIC,more complete in accurately simulating the biological effectiveness of photons and ion beams.On the other hand,with NASIC,cell survival models have been proposed based on DNA damage and chromosome aberration,respectively,which could be of valuable reference for the clinic of particle therapy.