Quantitative Insight into Responses of Cell Populations to Radiation Exposure

Idaho State University, Pocatello ID

Investigators

Abstract

Hanin 0109895 The goal of the project is to gain a new quantitative insight, on the basis of advanced mathematical methods, into kinetics of biological processes in irradiated cell populations. The investigator formulates and analyzes a comprehensive mechanistic mathematical model of these processes, including formation of radiation-induced lesions and their repair, misrepair and fixation, cell cycling and cell death. Mathematical modeling techniques include general age-dependent branching stochastic processes, queueing systems, stochastic simulation, and modern methods of statistical inference. Parameters of the model are estimated from experimental data on kinetics and survival of cells in synchronized cultures of S3 HeLa and V79 cells exposed to continuous irradiation at various dose rates. Parameter estimation is based on a comprehensive stochastic simulation model of the underlying biological processes and on methods of stochastic optimization in the maximum likelihood setting. The model is applied to stationary and exponential cell cultures that serve as experimental counterparts of tumor cell populations at different stages of tumor development. The distribution of the number of surviving clonogenic cells at the end of radiation exposure, obtained from the comprehensive simulation model of cell population kinetics, is compared with explicit formulas for this distribution within simpler birth and death Markov models that resulted from the preliminary studies. The most important biological outcome of this work consists of the set of estimates of unobservable model parameters, which are interpretable in biologically appealing terms of repair processes and cell kinetics. The project has a significant impact on evaluation, prediction and optimization of the efficacy of radiation cancer treatment and associated methods of cure rate estimation. A remarkable progress in cell biology and radiation biology since the 1920's has resulted in a prodigious amount of experimental data comprising all aspects of cell responses to ionizing radiation. These data represent an invaluable source of information for furthering our knowledge about intracellular processes in normal and irradiated cells. However, to a large extent, this gold mine of experimental findings amassed over years remains unclaimed. The investigator and his collaborators attempt to understand and describe mathematically the most basic processes in normal and irradiated cells. This is accomplished on the basis of advanced mathematical, statistical and computational methods applied to the original experimental data describing responses of several cell lines to radiation exposure at variable dose rate. The project was triggered by and has far-reaching implications for cancer radiotherapy.