Linear Energy Transfer (LET) is the main physical parameter to compare charged particles to photons and predict the higher biological effectiveness of the former radiation. Cytogenetic damage complexity governs cellular radioresponse and reflects the peculiar manner with which energy is deposited by ions as described by the Bragg curve, and is therefore likely to change along ion penetration depth and with its track structure. Hence, ion beams of different Z but similar LETs may differ radiobiologically and construction of ???biological??? Bragg curves may improve modeling of this type of radiation. Moreover, there are still uncertainties on charged-particle non-cancer effects of relevance in cancer hadrontherapy. In fact, most experimental data are almost exclusively on tumour cell lethality and on the Spread-Out Bragg Peak (SOBP), overlooking sub-lethal damage induction on normal cells at various positions along the Bragg curve. Further, very little is known on non-targeted effects (NTE) by ion-irradiated normal cells expressing long-term sub-lethal damage. We studied the onset of Stress-Induced Premature Senescence (SIPS) by ???-galactosidase assay and the induction of chromosome aberrations (CA) by whole-chromosome FISH painting and mFISH along the Bragg curve for several ion beams on three normal cell lines (AG01522 fibroblasts, MCF-10A breast epithelial cells and endothelial HUVEC cells). Occurrence of NTE by medium-transfer design from irradiated prematurely senescing cells was studied at different time points after irradiation on unirradiated MCF10A and breast cancer epithelial MCF7 cells. End-of-track effects of up to 20 MeV 12C and 16O beams were studied at the 3-MV Tandem accelerator, Department of Physics, Naples; 60 MeV/u 16O and 20Ne beams were used at INFN-LNS cyclotron, Catania, to explore changing biological effectiveness along the Bragg curve. Data show SIPS being very effectively induced by ion irradiation, with a qualitative and quantitative dependence on ion type and Bragg curve position, persisting for up to 2 months post exposure. CA data also indicate a similar dependence: the elevated incidence of complex-type rearrangements as revealed by mFISH well agrees with these aberrations being a cytogenetic signature of high-LET radiation. However, the overall incidence of CA and SIPS point to a significantly greater efficiency of ion beams compared to x-rays even at very high LETs, contrary to the notion of a close-to-unity RBE above 200 keV/???m. The onset of SIPS at ion beam entrance may have important implications for hadrontherapy cancer patients. Finally, we observed a significant bystander effect by senescing cells manifesting itself with an increase in tumour cell proliferation, in agreement with in vivo reports of a Senescence-Associated Secretory Phenotype. Monte-Carlo modeling by Geant4 code is under way to correlate ion-track structure with such results.

In vitro sub-lethal and non-targeted effects on normal human cells along the Bragg curve for different ion beams

CAMPAJOLA, LUIGI;GROSSI, GIANFRANCO;MANTI, LORENZO
2013

Abstract

Linear Energy Transfer (LET) is the main physical parameter to compare charged particles to photons and predict the higher biological effectiveness of the former radiation. Cytogenetic damage complexity governs cellular radioresponse and reflects the peculiar manner with which energy is deposited by ions as described by the Bragg curve, and is therefore likely to change along ion penetration depth and with its track structure. Hence, ion beams of different Z but similar LETs may differ radiobiologically and construction of ???biological??? Bragg curves may improve modeling of this type of radiation. Moreover, there are still uncertainties on charged-particle non-cancer effects of relevance in cancer hadrontherapy. In fact, most experimental data are almost exclusively on tumour cell lethality and on the Spread-Out Bragg Peak (SOBP), overlooking sub-lethal damage induction on normal cells at various positions along the Bragg curve. Further, very little is known on non-targeted effects (NTE) by ion-irradiated normal cells expressing long-term sub-lethal damage. We studied the onset of Stress-Induced Premature Senescence (SIPS) by ???-galactosidase assay and the induction of chromosome aberrations (CA) by whole-chromosome FISH painting and mFISH along the Bragg curve for several ion beams on three normal cell lines (AG01522 fibroblasts, MCF-10A breast epithelial cells and endothelial HUVEC cells). Occurrence of NTE by medium-transfer design from irradiated prematurely senescing cells was studied at different time points after irradiation on unirradiated MCF10A and breast cancer epithelial MCF7 cells. End-of-track effects of up to 20 MeV 12C and 16O beams were studied at the 3-MV Tandem accelerator, Department of Physics, Naples; 60 MeV/u 16O and 20Ne beams were used at INFN-LNS cyclotron, Catania, to explore changing biological effectiveness along the Bragg curve. Data show SIPS being very effectively induced by ion irradiation, with a qualitative and quantitative dependence on ion type and Bragg curve position, persisting for up to 2 months post exposure. CA data also indicate a similar dependence: the elevated incidence of complex-type rearrangements as revealed by mFISH well agrees with these aberrations being a cytogenetic signature of high-LET radiation. However, the overall incidence of CA and SIPS point to a significantly greater efficiency of ion beams compared to x-rays even at very high LETs, contrary to the notion of a close-to-unity RBE above 200 keV/???m. The onset of SIPS at ion beam entrance may have important implications for hadrontherapy cancer patients. Finally, we observed a significant bystander effect by senescing cells manifesting itself with an increase in tumour cell proliferation, in agreement with in vivo reports of a Senescence-Associated Secretory Phenotype. Monte-Carlo modeling by Geant4 code is under way to correlate ion-track structure with such results.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/597326
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