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Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice

Vincent FavaudonInstitut Curie, Centre de Recherche, 91405 Orsay, FranceLaura CaplierPathology Laboratory, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, 94704 Maisons Alfort, FranceVirginie MonceauInstitut Gustave RoussyFrédéric PouzouletInstitut Curie, Centre de Recherche, 91405 Orsay, FranceMano SayarathInstitut Curie, Centre de Recherche, 91405 Orsay, FranceCharles FouilladeInstitut Curie, Centre de Recherche, 91405 Orsay, FranceMarie‐France PouponInstitut Curie, Centre de Recherche, 91405 Orsay, FranceIsabel Martínez BritoINSERM U900, 75248 Paris 05, FrancePhilippe HupéInstitut Curie, Centre de Recherche, 75248 Paris 05, FranceJean BourhisUniversité Paris-XI, 91405 Orsay, FranceJanet HallInstitut Curie, Centre de Recherche, 91405 Orsay, FranceJean‐Jacques FontainePathology Laboratory, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, 94704 Maisons Alfort, FranceMarie‐Catherine VozeninUniversity Hospital of Lausanne

2014en

ABI

Annotatsiya

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.

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DOI: 10.1126/scitranslmed.3008973

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