Modelling Irradiation-Induced Cell Cycle Delays

In studies preceding this project we have documented [1, 2, 3] the relationship between the high lET radiationinduced mitotic delay and the expression of chromosome damage. In particular, a direct correlation between the average time to enter the mitosis and aberration burden has been claimed [3]. To further elucidate the complexity of cell cycle arrest after exposure to high LET irradiation, we have developed a Monte Carlo simulation model which combines the cell cycle progression through G1, S and G2/M phases with the experimental cytogenetic data [2]. Based on experimentally accessible information about the cell kinetics as measured by the mitotic index (cf. Fig.1), the aim of our project is to quantify checkpoints activity and to reproduce the cell cycle perturbations as expressed by a damage-correlated time-delay. To establish quantitative relationship between aberrations formed in interphase and visible in metaphase, cell passage through mitotic cycle stages has been simulated by means of a kinetic model in which duration of each of 4 cycle phases, ph = {G1, S,G2,M}, is taken as a log-normal stochastic value characterized by its mean and dispersion. For V79 Chinese hamster cells, as used in our simulations, the mean duration times [1] of the cell cycle phases are tG1 = 2.25 h, tS = 6.5 h, tG2 = 1.5 h, tM = 0.75h. The phase duration for an individual cell is given by a certain probability distribution Dph(τ) where τ is a time which a given cell had already spent in the current phase. Consequently, a single cell of phase age τ is assumed to leave its current phase within a time interval [τ, τ + dτ ] with probability Dph(τ)dτ and a mean number of cells dNph→(t) leaving the phase ph within an infinitesimal time interval [t, t+ dt] is defined by the mean flux dNph→(t) dt . On the other hand, if we trace the behavior of a particular cell, we can define Dph(τ) as the probability distribution of leaving the phase at age τ , provided that the cell had not completed the phase earlier, i.e.,Dph(τ) = Fph(τ) 1− ∫ τ