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: 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.DNA Repair 01/2015; 27C. DOI:10.1016/j.dnarep.2015.01.002 · 3.36 Impact Factor
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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. DOI:10.1007/s00411-009-0239-7 · 1.58 Impact Factor
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ABSTRACT: The current widely used biological equivalent dose (BED) formalism for permanent implants is based on the linear-quadratic model that includes cell repair and repopulation but not resensitization (redistribution and reoxygenation). The authors propose a BED formalism that includes all the four biological effects (4Rs), and the authors propose how it can be used to calculate appropriate prescription doses for permanent implants with Cs-131. A resensitization correction was added to the BED calculation for permanent implants to account for 4Rs. Using the same BED, the prescription doses with Au-198, I-125, and Pd-103 were converted to the isoeffective Cs-131 prescription doses. The conversion factor F, ratio of the Cs-131 dose to the equivalent dose with the other reference isotope (Fr: with resensitization, Fn: without resensitization), was thus derived and used for actual prescription. Different values of biological parameters such as α, β, and relative biological effectiveness for different types of tumors were used for the calculation. Prescription doses with I-125, Pd-103, and Au-198 ranging from 10 to 160 Gy were converted into prescription doses with Cs-131. The difference in dose conversion factors with (Fr) and without (Fn) resensitization was significant but varied with different isotopes and different types of tumors. The conversion factors also varied with different doses. For I-125, the average values of Fr/Fn were 0.51/0.46, for fast growing tumors, and 0.88/0.77 for slow growing tumors. For Pd-103, the average values of Fr/Fn were 1.25/1.15 for fast growing tumors, and 1.28/1.22 for slow growing tumors. For Au-198, the average values of Fr/Fn were 1.08/1.25 for fast growing tumors, and 1.00/1.06 for slow growing tumors. Using the biological parameters for the HeLa/C4-I cells, the averaged value of Fr was 1.07/1.11 (rounded to 1.1), and the averaged value of Fn was 1.75/1.18. Fr of 1.1 has been applied to gynecological cancer implants with expected acute reactions and outcomes as expected based on extensive experience with permanent implants. The calculation also gave the average Cs-131 dose of 126 Gy converted from the I-125 dose of 144 Gy for prostate implants. Inclusion of an allowance for resensitization led to significant dose corrections for Cs-131 permanent implants, and should be applied to prescription dose calculation. The adjustment of the Cs-131 prescription doses with resensitization correction for gynecological permanent implants was consistent with clinical experience and observations. However, the Cs-131 prescription doses converted from other implant doses can be further adjusted based on new experimental results, clinical observations, and clinical outcomes.Medical Physics 02/2014; 41(2):024101. DOI:10.1118/1.4860255 · 3.01 Impact Factor