A microdosimetric-kinetic model of cell death from exposure to ionizing radiation of any LET, with experimental and clinical applications

Abstract

A model of mammalian cell death and survival following exposure to ionizing radiation that combines a kinetic description of repair and injury processes with a microdosimetric description of radiation energy deposition is presented. With reduction of one of the defining kinetic equations from quadratic to linear form, relations are obtained that describe the results of commonly performed variations of the cell survival experiment. These include single-dose survival of linear-quadratic form, survival after split-dose treatment and after post-irradiation change ill culture conditions and survival after exposure to continuously administered irradiation at low constant dose-rate. The effect of the inhomogeneous deposition of radiation energy inherent in exposure to radiation of significantly non-zero LET is included in these relations which apply to radiation of any LET. The values of the kinetic rate and time constants for repair and the processes that lead to cell death postulated in the model, which compose the alpha and beta parameters of the linear-quadratic survival relation, are estimated from cell survival experiments and DNA double-strand break measurements from the literature. A relation for estimating the daily fractional dose equivalent to continuous irradiation as employed in low dose-rate brachytherapy cancer treatment is presented.

Analytical Description of the LET Dependence of Cell Survival Using the Repairable-Conditionally Repairable Damage Model

“…When the RCR parameters are of the form shown in Eqs. (9), (10) and (11), the behavior of the RCR model is in agreement with expected biological mechanisms. For instance, the fraction of cells being damaged decreases at high LETs for a constant dose level, as can be seen in Fig.…”

“…At GSI, the local effect model (LEM) (9) is used to estimate the biological effect of carbon ions by using the X-ray survival curve obtained with a modified LQ model and the local dose derived from an amorphous track structure model. The microdosimetric kinetic (MK) model of Hawkins (10,11) is similar to the LEM in the sense that in both of the models the cell nucleus, which is assumed to be the principal target, is considered to consist of numerous small independent subunits. Furthermore, as in the LEM, the theory behind the MK model is based on the postulates that the LQ cell survival function can be used for the subunits of the nucleus and that the response to ions is obtained by summation of the local effect over the whole nucleus.…”

The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR

“…However, this strategy is in line with other modeling approaches as reported e.g. in [30][31][32][33] that despite of their biological simplifications allow to represent the major aspects of radiation effects surprisingly well.…”

“…With that, we follow a strategy that has already been successful in similar attempts e.g. to model the effects of high-LET radiation [14,30,33] or high-and low-energy photon radiation [27,54] based on a small set of parameters. Similarly, we here follow the strategy to find the optimal balance between simplicity and accuracy, i.e.…”

New Features of the Particle and Heavy Ion Transport Code System; PHITS

“…As an example of the application of this tally, we have calculated the biological dose for charged particle therapy using this tally coupled to the microdosimetric kinetic (MK) model. 6) In the MK model, the RBE of charged particles can be determined from the probability densities of y in tumor, which can be calculated by the SED tally of PHITS within reasonable computational time. The results of the biological dose estimated by this method agree in general within 20% error with the several experimental data obtained by irradiating a slab phantom by the spread-out Bragg peak beams as well as several mono energetic heavy ions up to 400 MeV/n.…”