Computational Studies of DNA Fragmentation Process During and After Radiation Therapy

Cancer is a leading cause of death worldwide. Delivering high-energy photons, or other particles to the tumor is one of the common cancer treatment methods. In a microscopic perspective, the radiation damages the genomic contents (DNA) of the tumor cell. Every DNA damage is categorized into a few different groups among which the Double Strand Breaks (DSB) are more lethal for the target cells and are the main focus of this study. DSBs are subject to both repair and misrepair with different probabilities depending on the type of damage, tumor cell line, and the biophysiological conditions in the surrounding irradiated area. The "UNIfied and VERSatile bio-response Engine" (UNIVERSE) is a mechanistic modeling framework that has been developed by BioPT group at Heidelberg Ion-Beam Therapy Center(HIT) with the goal of enabling the description of clinically relevant modifying factors of radiation action for both conventional and ion beam irradiations. In this thesis work, the model "UNIVERSE" has been extended in order to simulate the DNA Fragmentation process considering the DNA damage and repair kinetics in the presence of different oxygen concentration levels in cellular environment taking various dose levels and dose rates of conventional radiations into account. After simulating the number of DSBs induced by the radiation, the DSBs are distributed over the DNA locally related to various Giant Loops (GL) considering the physical properties of the photon-matter interaction and its relevant statistical behaviour. Thereafter, the positions of all unrepaired DSBs located inside every single GL are determined, which leads to the calculation of the length of DNA Fragments detached from the sugar-phosphate backbone of the DNA. The influence of different radiation dose levels on DNA fragmentation process has been studied and the results have been compared to the experimental data taken from some relevant literature. Since the benchmarking process has succeeded and shown a good correspondence between the results of simulation and experimental data, the further steps with the goal of analyzing the effect of different dose rates and oxygen concentrations at surrounding irradiated area on DNA fragmentation process for a given dose level have been conducted. The study also encompasses an investigation into the potential manifestation of the Sparing and FLASH effects when subjecting normal and tumor cell lines to irradiation at Ultra High Dose Rates (uHDR) under hypoxic conditions.