Abstract
A biophysical model of radiation-induced cell death and chromosome aberrations [called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA)] was further developed and applied to therapeutic protons. The model assumes a pivotal role of DNA cluster damage, which can lead to clonogenic cell death following three main steps: (i) a DNA “cluster lesion” (CL) produces two independent chromosome fragments; (ii) fragment mis-rejoining within a threshold distance d gives rise to chromosome aberrations; (iii) certain aberration types (dicentrics, rings, and large deletions) lead to clonogenic inactivation. The yield of CLs and the probability, f, that a chromosome fragment remains un-rejoined even if other fragment(s) are present within d, were adjustable parameters. The model, implemented as a MC code providing simulated dose–responses directly comparable with experimental data, was applied to pristine and modulated Bragg peaks of the proton beam used to treat eye melanoma at INFN-LNS in Catania, Italy. Experimental survival curves for AG01522 cells exposed to the Catania beam were reproduced, supporting the model assumptions. Furthermore, cell death and chromosome aberrations at different depths along a spread-out Bragg peak (SOBP) dose profile were predicted. Both endpoints showed an increase along the plateau, and high levels of damage were found also beyond the distal dose fall-off, due to low-energy protons. Cell death and chromosome aberrations were also predicted for V79 cells, in the same irradiation scenario as that used for AG01522 cells. In line with other studies, this work indicated that assuming a constant relative biological effectiveness (RBE) along a proton SOBP may be sub-optimal. Furthermore, it provided qualitative and quantitative evaluations of the dependence of the beam effectiveness on the considered endpoint and dose. More generally, this work represents an example of therapeutic beam characterization avoiding the use of experimental RBE values, which can be source of uncertainties.
Highlights
According to the Particle Therapy Co-operative Group1, 49 proton therapy centers were operating and 32 were under construction in June 2015
After comparing simulated dose–response curves for chromosome aberrations with experimental data taken from the literature, the model was applied to the 62-MeV proton beam used to treat ocular melanoma at the CATANA facility of Institute of Nuclear Physics (INFN)-LNS in Catania, Italy [16]
The BIANCA model is based on the following assumptions: [1] radiation induces DNA “cluster lesions” (CLs), and each cluster lesion” (CL) gives rise to two independent chromosome fragments; [2] two chromosome fragments can undergo rejoining only if their initial distance is smaller than a threshold distance d, leading to chromosome aberrations in case of mis-rejoining; and [3] dicentrics, rings, and large deletions lead to clonogenic cell death
Summary
According to the Particle Therapy Co-operative Group proton therapy centers were operating and 32 were under construction in June 2015. Protons are usually considered low-LET radiation, and a constant relative biological effectiveness (RBE) of 1.1, mainly derived from animal experiments, is generally applied in the clinical practice. Both in vitro and in vivo studies indicate that proton effectiveness increases with decreasing energy, which is increasing LET. The RBE depends on the particle energy and on many other factors, including dose, dose-rate, cell type, and biological endpoint Both in vitro and in vivo data show a significant RBE increase for lower fractional doses [e.g., Ref. It should be considered that, the main endpoint of interest for tumor cells is cell death, other endpoints (e.g., mutations, non-lethal chromosome aberrations, etc.) might be relevant for normal tissues
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call