Modeling cellular responses to low-dose radiation and their medical implications

• Author / Creator

  Oluwole Victor Olobatuyi

• Ionizing radiation is widely used in treatment and medical diagnosis. Doses in the range of 1.5 Gy to 10 Gy are used in radiation treatment of cancer. Lower doses (less than 1.5 Gy) are used in medical imaging, and also are incurred by tissues that are near irradiated target volumes. The impact of treatment doses on healthy and pathological tissues has been analyzed in great detail and sophisticated mathematical models have been developed. A successful model, for example, is the so-called Linear Quadratic (LQ) model, which describes the survival fraction of cells as a function of radiation dose.Recent experimental studies on low-dose radiation of tissue have shown a discrepancy with the standard LQ model; cell damage is much larger than expected by the LQ model. This phenomenon has been called hyper-radiosensitivity and increased radioresistance (HRS/IRR).In this thesis, I develop and analyze mathematical models to understand the HRS/IRR phenomenon, and to analyze corresponding experimental data on low-dose radiation. I focus on two primary biological hypotheses, namely the radiation-induced bystander effects and the cell-cycle G2-checkpoint effects. I show that both hypotheses are able to explain the HRS/IRR phenomenon.The bystander effects (BEs) are consequences of distress signals (also known as the bystander signals) that are emitted by radiation-damaged cells. The model for the BEs is a complex system of reaction-diffusion partial differential equations (PDEs), which incorporates BEs like bystander signal-induced death and damage, and the bystander signal-dependent repair. I fit this model to experimental data and estimate model parameters. I analyze the steady states of this model and I identify long transients in the dynamics of bystander signals, consistent with biological observations. Moreover, I show the existence and uniqueness of weak solutions, and the existence of a compact global attractor for the system of PDE. Additionally, I analyze the effect of bystander signals on invasion of cancer into healthy tissue and I show that the bystander signal can accelerate cancer invasion.On the other hand, the cell cycle G2-checkpoint is a regulatory mechanism that ensures that damaged cells in G2 phase of the cell cycle are repaired before progressing to the next phase. Experiments have shown that some damaged cells evade the G2 checkpoint, which result in cell death in the next phase. The model for the G2-checkpoint effects is derived from cell-cycle dynamics and this model can also explain the HRS/IRR phenomenon as observed in experiments on several cell lines. In fact, I have been able to derive explicit formulas that relate the HRS/IRR phenomenon to their underlying cell-cycle events, as well as to the surviving fraction at 2 Gy. This work has been able to resolve such a highly debated relationship.Considering two possible explanations for the HRS/IRR phenomenon, I found evidence in the literature that these effects (bystander and G2-checkpoint) are mutually exclusive. For a given cell line, typically only one of these effects is important.The HRS/IRR is a serious concern for tissues that are exposed to low-dose radiation and the low-dose risk assessment will have to be updated. On the other hand, low-dose radiation might suggest novel therapies for cancer treatment that benefit from a better understanding of the HRS/IRR phenomenon.

• Subjects / Keywords

  • Radiation Oncology
  • Partial Differential Equations
  • Mathematical modeling

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3959CQ4P

• License

  Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.