[Ultrahigh dose-rate, "flash" irradiation minimizes the side-effects of radiotherapy].
OBJECTIVE
Pencil beam scanning and filter free techniques may involve dose-rates considerably higher than those used in conventional external-beam radiotherapy. Our purpose was to investigate normal tissue and tumour responses in vivo to short pulses of radiation.


METHODS
C57BL/6J mice were exposed to bilateral thorax irradiation using pulsed (at least 40 Gy/s, flash) or conventional dose-rate irradiation (0.03 Gy/s or less) in single dose. Immunohistochemical and histological methods were used to compare early radio-induced apoptosis and the development of lung fibrosis in the two situations. The response of two human (HBCx-12A, HEp-2) tumour xenografts in nude mice and one syngeneic, orthotopic lung carcinoma in C57BL/6J mice (TC-1 Luc+), was monitored in both radiation modes.


RESULTS
A 17 Gy conventional irradiation induced pulmonary fibrosis and activation of the TGF-beta cascade in 100% of the animals 24-36 weeks post-treatment, as expected, whereas no animal developed complications below 23 Gy flash irradiation, and a 30 Gy flash irradiation was required to induce the same extent of fibrosis as 17 Gy conventional irradiation. Cutaneous lesions were also reduced in severity. Flash irradiation protected vascular and bronchial smooth muscle cells as well as epithelial cells of bronchi against acute apoptosis as shown by analysis of caspase-3 activation and TUNEL staining. In contrast, the antitumour effectiveness of flash irradiation was maintained and not different from that of conventional irradiation.


CONCLUSIONS
Flash irradiation shifted by a large factor the threshold dose required to initiate lung fibrosis without loss of the antitumour efficiency, suggesting that the method might be used to advantage to minimize the complications of radiotherapy.
Institut Curie, centre universitaire, bâtiment 110, rue Henri-Becquerel, 91405 Orsay cedex, France; Inserm U612, centre universitaire, bât. 110, 91405 Orsay, France; Inserm U1021, centre universitaire, bât. 110, 91405 Orsay, France; CNRS UMR 3347, centre universitaire, bât. 110, 91405 Orsay, France; Université Paris-Sud, centre universitaire, 91405 Orsay, France. Electronic address: vincent.favaudon@curie.fr.
V
V
Favaudon
Institut Curie, centre universitaire, bâtiment 110, rue Henri-Becquerel, 91405 Orsay cedex, France; Inserm U612, centre universitaire, bât. 110, 91405 Orsay, France; Inserm U1021, centre universitaire, bât. 110, 91405 Orsay, France; CNRS UMR 3347, centre universitaire, bât. 110, 91405 Orsay, France; Université Paris-Sud, centre universitaire, 91405 Orsay, France.
C
C
Fouillade
Laboratoire de radio-oncologie, centre hospitalier universitaire Vaudois, 1011 Lausanne, Suisse.
M-C
MC
Vozenin
D000818:Animals; D008175:Lung Neoplasms / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000517:prevention & control; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods; D011879:Radiotherapy Dosage
Apoptose; Apoptosis; Complication; Fibrose; Fibrosis; Flash; Haut débit de dose; Lung; Mouse; Poumon; Radiation; Souris; TGF; Tumeur; Tumour; Ultra-high dose-rate