Cellular Premature Senescence And Chromosome Aberrations In Normal Human Cell Lines Exposed To The Cnao Carbon Ion Therapeutic Beam

Although the evolutionarily acquired role by cellular senescence as a powerful tumour suppressor is well acknowledged, ectopically senescing cells may exert deleterious effects on the tissue microenvironment, the most prominent of which is the so-called senescence-associated secretory phenotype (SASP), by which senescing cells may promote tumour progression. Chromosome aberrations, on the other hand, are the most validated biomarker for cancer risk and provide useful insights on mechanistical modes of ionising radiation action. The recently operational National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO) is the first Italian facility for cancer treatment with carbon ions. The main justification for the medical use of high –LET radiations rely on their greater effectiveness at tumour cell killing compared to low-LET radiations or lighter charged particles such as protons. Despite encouraging results on local tumour control from other centres worldwide that have adopted this therapeutic strategy, there still exists uncertainties surrounding late effects in the normal tissue. These can be brought about by sublethally damaged cells, such as those that enter senescence prematurely or those carrying transmissible genetic damage, which may lead to organ dysfunction/tissue disruption and secondary cancers. Therefore, we have studied the onset of premature cellular senescence by -galactosidase expression in post-irradiation serially cultivated cells as well as the induction of structural chromosome aberrations detected by FISH techniques in chemically-induced (calyculin A) metaphases 24 h after radiation exposure. Normal endothelial and epithelial cells were exposed to a 6-cm Spread Out Bragg Peak (SOBP) carbon ion beam (E = 246-312 MeV/n) at CNAO. Two doses (0.5 and 2 Gy) were delivered at various depths along the beam, with LET values ranging from 14 keV/m at the entrance to 100 keV/m at the distal SOBP position. Results will be illustrated and their implications for carbon-ion radiotherapy discussed.