title: Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.
abstract: 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.
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France. vincent.favaudon@curie.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Favaudon
authors.affiliation: Pathology Laboratory, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, 94704 Maisons Alfort, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Caplier
authors.affiliation: Université Paris-XI, 91405 Orsay, France. INSERM U1030, Institut Gustave-Roussy, 94805 Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Monceau
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pouzoulet
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
authors.forename: Mano
authors.initials: M
authors.lastname: Sayarath
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Fouillade
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.affiliation: Institut Curie, Centre de Recherche, 75248 Paris 05, France. INSERM U900, 75248 Paris 05, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Brito
authors.affiliation: Institut Curie, Centre de Recherche, 75248 Paris 05, France. INSERM U900, 75248 Paris 05, France. Mines ParisTech, 77305 Fontainebleau, France. CNRS, UMR144, 75248 Paris 05, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hupé
authors.affiliation: Université Paris-XI, 91405 Orsay, France. INSERM U1030, Institut Gustave-Roussy, 94805 Villejuif, France. Radio-Oncologie/Radiothérapie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
authors.affiliation: Pathology Laboratory, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, 94704 Maisons Alfort, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fontaine
authors.affiliation: Université Paris-XI, 91405 Orsay, France. INSERM U1030, Institut Gustave-Roussy, 94805 Villejuif, France. Radio-Oncologie/Radiothérapie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. INSERM U967, Commissariat à l'Énergie Atomique (CEA), Division des Sciences du Vivant (DSV), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), 92265 Fontenay aux Roses, France.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001808:Blood Vessels / Q000528:radiation effects; D001980:Bronchi / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000473:pathology; D023041:Xenograft Model Antitumor Assays