Resensitization due to redistribution of cells in the phases of the cell cycle during arbitrary radiation protocols.
ABSTRACT When a cell population in exponential growth is subjected to ionizing radiation, the degree to which its long-term size is attenuated, relative to a control population that is not irradiated, depends not only on the total dose but also on the time pattern of dose delivery. Using a standard mathematical model for cycling cell populations with age-dependent radiosensitivity, it has recently been shown that normal progression of cells through the cycle tends to decrease this relative population size when the total dose delivery time is increased from essentially zero times to short, finite times (Chen et al., Math. Biosci. 126, 147-170, 1995). This mathematical result is an agreement with intuitive arguments and experiments long known in radiobiology. Mechanistically, it says that after the first part of a dose has preferentially eliminated the more sensitive cells of an exponentially cycling cell population, cell cycle progression, with the consequent redistribution of cells among cycle phases, tends to "resensitize" that population, an affect countering that of sublethal damage repair. The present paper now generalizes this result, demonstrating that the redistribution-induced increase of cell killing carries over to doses of arbitrary duration. That is to say, delivering a given dose over some extended period will result in lesser ultimate population size (i.e. population size measured at some fixed time long after irradiation has ceased) than will delivering the same total dose acutely. The redistribution-induced resensitization occurs no matter how radiosensitivity depends on cell age. For illustration, examples are given to show that, for a split dose, the least sensitivity is observed when the two doses coincide. These examples also demonstrate, within the constraints of the overall resensitization principle, the possibility of an oscillatory dependence of population sensitivity on interfraction time.
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ABSTRACT: Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.PLoS Computational Biology 11/2013; 9(11):e1003295. · 4.87 Impact Factor
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ABSTRACT: Cover title. "June 1999." Includes bibliographical references (p. 19-26). Lawrence M. Wein, Jonathan E. Cohen.
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ABSTRACT: Ionizing radiation is known to delay the cell cycle progression. In particular after particle exposure significant delays have been observed and it has been shown that the extent of delay affects the expression of damage, such as chromosome aberrations. Thus, to predict how cells respond to ionizing radiation and to derive reliable estimates of radiation risks, information about radiation-induced cell cycle perturbations is required. In the present study we describe and apply a method for retrieval of information about the time-course of all cell cycle phases from experimental data on the mitotic index only. We study the progression of mammalian cells through the cell cycle after exposure. The analysis reveals a prolonged block of damaged cells in the G2 phase. Furthermore, by performing an error analysis on simulated data valuable information for the design of experimental studies has been obtained. The analysis showed that the number of cells analyzed in an experimental sample should be at least 100 to obtain a relative error <20%.Biophysik 09/2009; 48(4):361-70. · 1.70 Impact Factor