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Sci Transl Med. 2014 Jul 16;6(245):245ra93. doi: 10.1126/scitranslmed.3008973.

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

Author information

1
Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France. vincent.favaudon@curie.fr.
2
Pathology Laboratory, Ecole Nationale Vétérinaire d'Alfort, Université Paris-Est, 94704 Maisons Alfort, France.
3
Université Paris-XI, 91405 Orsay, France. INSERM U1030, Institut Gustave-Roussy, 94805 Villejuif, France.
4
Institut Curie, Centre de Recherche, 91405 Orsay, France. INSERM U612, 91405 Orsay, France.
5
Institut Curie, Centre de Recherche, 75248 Paris 05, France. INSERM U900, 75248 Paris 05, France.
6
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.
7
Université Paris-XI, 91405 Orsay, France. INSERM U1030, Institut Gustave-Roussy, 94805 Villejuif, France. Radio-Oncologie/Radiothérapie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
8
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.

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.

PMID:
25031268
DOI:
10.1126/scitranslmed.3008973
[Indexed for MEDLINE]
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