Resensitization due to Redistribution of Cells in the Phases of the Cell Cycle during Arbitrary Radiation Protocols

Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115, USA.
Radiation Research (Impact Factor: 2.91). 03/1996; 145(2):134-43. DOI: 10.2307/3579167
Source: PubMed


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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    • "For example, irradiation can lead to changes in the cell cycle distribution and the change in sensitivity corresponding to this " redistribution " is considered to be an important factor in fractionated radiotherapy [1] [2]. The impact of this potential sensitization as a consequence of the cell cycle redistribution has been investigated also in detail in modeling studies [3]. Many of the earlier radiobiological studies were focused on cell killing as the relevant endpoint to study the cell-cycle dependent sensitivity, utilizing synchronized cell populations prepared by various synchronization methods (e.g. "
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    ABSTRACT: The different DNA damage repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) have been linked to the variation of radiosensitivity throughout the cell cycle. However, no attempts have been made to test the various hypotheses derived from these studies in a quantitative way e.g. by using modelling approaches. Here we present the first modelling approach that allows predicting the cell cycle dependent radiosensitivity of repair proficient as well as of repair deficient cell lines after photon irradiation based on a small set of parameters and assumptions.
    Full-text · Article · Jan 2015 · DNA Repair
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    • "In many experiments a positive correlation between radiation dose and the duration of cell-cycle delays was found. Although such findings were usually quantified in terms of a linear relationship between phase duration and dose (Zaider and Minerbo (1993); Hahnfeldt and Hlatky (1996)), a more detailed analysis points to a direct correlation between cell cycle delay and the number of aberrations carried by a cell (Gudowska-Nowak et al (2005)). This effect is responsible for the loss of synchrony of the population and can be illustrated by interpreting the (normalized) mitotic index as a frequency histogram of times spent by cells before the actual division happens. "
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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%.
    Full-text · Article · Sep 2009 · Biophysik
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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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