The BIANCA model/code of radiation-induced cell death: application to human cells exposed to different radiation types

Abstract

This paper presents a biophysical model of radiation-induced cell death, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), based on the assumption that some chromosome aberrations (dicentrics, rings, and large deletions, called ‘‘lethal aberrations’’) lead to clonogenic inactivation. In turn, chromosome aberrations are assumed to derive from clustered, and thus severe, DNA lesions (called ‘‘cluster lesions,’’ or CL) interacting at the micrometer scale; the CL yield and the threshold distance governing CL interaction are the only model parameters. After a pilot study on V79 hamster cells exposed to protons and carbon ions, in the present work the model was extended and applied to AG1522 human cells exposed to photons, He ions, and heavier ions including carbon and neon. The agreement with experimental survival data taken from the literature supported the assumptions. In particular, the inactivation of AG1522 cells was explained by lethal aberrations not only for X-rays, as already reported by others, but also for the aforementioned radiation types. Furthermore, the results are consistent with the hypothesis that the critical initial lesions leading to cell death are DNA cluster lesions having yields in the order of *2 CL Gy-1 cell-1 at low LET and*20 CL Gy-1 cell-1 at high LET, and that the processing of these lesions is modulated by proximity effects at the micrometer scale related to interphase chromatin organization. The model was then applied to calculate the fraction of inactivated cells, as well as the yields of lethal aberrations and cluster lesions, as a function of LET; the results showed a maximum around 130 keV/lm, and such maximum was much higher for cluster lesions and lethal aberrations than for cell inactivation.

Modeling radiation-induced cell death: role of different levels of DNA damage clustering

“…More specifically, the following data sets were considered for comparison in the present work: V79 cells exposed to X-rays and protons (Folkard et al 1996), V79 cells exposed to c-rays and alpha particles (Cox et al 1977, Thacker et al 1979, Phoenix et al 2009), AG01522 cells exposed to X-rays and protons (Chaudhary et al 2014), AG01522 cells exposed to carbon ions (Kavanagh et al 2013), and AG1522 cells exposed to c-rays and iron ions (Tsuboi et al 1992). To make the comparison more informative, a few results published in previous works (Ballarini et al 2013(Ballarini et al , 2014 and references therein) were also included. Concerning V79 cells, it is worth mentioning that, due to the short doubling time, it is likely that the most fast growing cell variants will dominate during long-term culturing.…”

“…From top to bottom, V79 cells exposed to He ions of 20, 28, 50, 90 and 120 keV/lm; AG1522 cells exposed to 132 keV/ lm alpha particles. The lines are simulation outcomes, the points (with the corresponding error bars) are experimental data taken from the literature (Cox et al 1977;Thacker et al 1979 andPhoenix et al 2009 for V79 cells;Neti et al 2004 to carbon ions of 24, 40 and 50 keV/lm (Ballarini et al 2013), for AG1522 cells exposed to carbon ions of 76.3 and 108 keV/lm (Ballarini et al 2014), and for AG1522 cells exposed to Fe ions of 200 and 500 keV/lm (unpublished). Again, d was maintained at 5 lm, whereas the yields of cluster lesions, which were in the range *2-12 CL Gy -1 cell -1 , were adjusted separately for each curve.…”

“…In addition to the CL yields related to the present work, Fig. 5a also reports a few CL yields taken from previous works (Ballarini et al 2013(Ballarini et al , 2014.…”

“…A detailed description of the model and the simulation code is beyond the scope of this paper and can be found in previous works (Ballarini 2010;Ferrari et al 2011;Ballarini et al 2011Ballarini et al , 2013Ballarini et al , 2014Ballarini et al , 2015. The main issues will be summarized and discussed herein with focus on the basic model assumptions: (1) radiation induces DNA cluster lesions (CLs), each of these CLs giving rise to two independent chromosome free-ends; (2) only pairs of chromosome free-ends with initial distance below a threshold d can undergo end-joining, leading to chromosome aberrations in case of mis-rejoining; (3) dicentrics, rings and large deletions (see below for the deletion size) lead to clonogenic cell death.…”

“…Like in previous works (e.g., Ballarini et al 2013Ballarini et al , 2014, V79 cell nuclei were modeled as cylinders with circular base (height and radius: 6 lm), whereas AG1522 nuclei were modeled as cylinders with elliptical base (height 4 lm; major axis 20 lm; minor axis 10 lm). Also smaller values are reported in the literature for the thickness of these cell nuclei, but such values in general refer to electron microscopy measurements; more recent measurements based on confocal microscopy, especially in living cells, provide larger values.…”