Resonance effect in self-renewing tissues.

Abstract

It was predicted previously that a depletion of cell population depends extremely on the period of periodic phase-specific killing of cells and at periods near the integer multiple of the mean cell-cycle time there is a considerable reduction in treatment-induced decrease of cell-population size (resonance effect). This paper is devoted to theoretical and experimental analysis of the resonance effect in self-renewing tissues. The main biological assumptions underlying the idea of the resonance effect are discussed and then reformulated in terms of a mathematical model. The model describes kinetics of cell populations under periodic treatment by high doses of a phase-specific cytotoxic agent with blocking effect. The dependence of cell survival on cell-cycle parameters and parameters of treatment is studied and the results are presented in a suitable form for experimental testing and practical usage. The obtained results give a theoretical basis for using the resonance effect in a self-renewing tissue control study and estimation of cell-cycle parameters of various cells including morphologically unrecognizable ones. The quantitative comparison of the theoretical predictions with experimental data obtained for mice spleen colony forming units (CFUs), cells of mice small intestine epithelium as well L1210 leukemic cells is carried out. The excellent agreement between theoretical and experimental results is demonstrated and the estimations of cycle parameters of CFUs, cryptogenic and transit cells of mice intestine epithelium are obtained. Biological consequences of the obtained results are discussed and the new hypothesis relative to self-renewing tissue proliferative control is put forward.