A Model of Radiation-Induced Cell Killing: Insights into Mechanisms and Applications for Hadron Therapy

A mechanism-based, two-parameter biophysical model of cell killing was developed, with the aim of elucidating the mechanisms underlying radiation-induced cell death and predicting cell killing by different radiation types, including protons and carbon ions at energies and doses of interest for cancer therapy. It was assumed that certain chromosome aberrations (dicentrics, rings and large deletions, called “Lethal Aberrations”) lead to clonogenic inactivation, and that aberrations derive from µm-scale misrejoining of chromatin fragments, which in turn are produced by “dirty” double-strand breaks called “Cluster Lesions” (CLs); the average number of CLs per Gy and per cell was left as a semi-free parameter, whereas the threshold distance for chromatin-fragment rejoining was the second parameter. The model, “translated” into a Monte Carlo code providing simulated survival curves, was compared with survival data on V79 cells exposed to protons and carbon ions, as well as X-rays. The agreement between simulations and data validated the model and supported the assumptions; in particular, at least for doses up to few Gy, dicentrics, rings and large deletions were found to be lethal not only for AG1522 cells exposed to X-rays, as already reported by others, but also for V79 cells exposed to protons and carbon ions of different energies. Furthermore, the derived CL yields suggest that the critical DNA lesions leading to clonogenic inactivation are more complex than “clean” DSBs. Following validation, the model was applied to characterize the particle- and LET-dependence of proton and carbon cell-killing. Consistent with the proton data, the predicted fraction of inactivated cells after 2-Gy protons was 40-50% below 7.7 keV/µm, increased by a factor 1.6 between 7.7 and 30.5 keV/µm, and decreased by a factor 1.1 between 30.5 and 34.6 keV/µm. These LET values correspond to proton energies below a few MeV, which are always present in the distal region of hadrontherapy Spread-Out Bragg Peaks (SOBP); especially when critical organs are present beyond the tumour, this should be taken into account in clinics. Consistent with the carbon data, the predicted fraction of inactivated cells after 2-Gy carbon was 40-50% between 13.7 and 32.4 keV/µm, it increased by a factor 1.7 between 32.4 and 153.5 keV/µm, and decreased by a factor 1.1 between 153.5 and 339.1 keV/µm. Finally, the model was applied to predict cell death at different depths along a carbon SOBP used for pre-clinical experiments at HIMAC in Chiba (Japan); the predicted fraction of inactivated cells was found to be roughly constant (less than 10%) along the SOBP, suggesting that this approach may be applied to predict cell killing by therapeutic beams and that, more generally, dicentrics, rings and deletions at the first mitosis may be regarded as a “biological dose”. This work allowed to shed light on the mechanisms of radiation-induced cell death, to characterize the particle- and LET-dependence of proton and carbon cell-killing, and to predict cell death along a carbon SOBP. More generally, a mechanism-based tool was developed that in some minutes can predict cell inactivation by protons or carbon ions of a given energy and dose, basing on an experimental photon curve and, in principle, a single (experimental) survival point for the considered ion type and energy. The model does not use RBE values, which can be a source of uncertainties.