Intravenous basic fibroblast growth factor protects the lung but not mediastinal organs against radiation-induced apoptosis in vivo.
OBJECTIVE
We evaluated the therapeutic potential of intravenously injected basic fibroblast growth factor against the lethal syndromes associated with irradiation of intrathoracic organs and assessed whether such protection might be associated with inhibition of programmed cell death (apoptosis) in the exposed tissues.


METHODS
C3H/HeJ and C3H/scid mice received either whole-chest, mediastinal, or bilateral lung irradiation. Human recombinant basic fibroblast growth factor was injected intravenously at doses of 400 ng immediately before and after irradiation, and then at 1 hour and 2 hours later. Time-adjusted survival was calculated from the date of irradiation by the product-limit Kaplan-Meier method. Detection of apoptotic changes in paraffin sections was performed by the DNA terminal transferase nick-end translation method.


RESULTS
Basic fibroblast growth factor protected the lungs but not other intrathoracic organs against radiation-induced damage. When radiation was restricted to the lungs, the LD50/180 from radiation pneumonitis was 20.75 Gy and increased to 23.0 Gy in basic fibroblast growth factor-treated mice. When the whole thorax was irradiated, basic fibroblast growth factor partially protected against pneumonitis at the low range of radiation doses (< or = LD50/180), but failed to confer protection at higher doses, nor did it protect against lethal radiation esophagitis. Staining for the presence of apoptotic nuclei revealed time- and radiation dose-dependent development of apoptosis in endothelial cells of the pulmonary capillary network, endocardium, and mesothelial cells of the pleura and pericardium. Although basic fibroblast growth factor inhibited apoptosis in the microvascular endothelium and the endocardium, it had no effect on apoptosis in the serosal mesothelium of the pleura and pericardium.


CONCLUSIONS
Intravenous basic fibroblast growth factor protects against the apoptotic microvascular component of early-phase radiation pneumonitis but may have no effect on other elements of the primary damage produced by radiation in the lungs and other intrathoracic organs. Understanding the patterns and temporal evolution of radiation-induced apoptosis and basic fibroblast growth factor-mediated antiapoptotic effects in thoracic organs and tumors may offer opportunities for pharmacologic intervention in the radiotherapeutic management of primary and metastatic lung tumors.
Fuks
Z
Z
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Alfieri
A
A
Haimovitz-Friedman
A
A
Seddon
A
A
Cordon-Cardo
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*; D008297:Male; D008482:Mediastinum; D051379:Mice; D008809:Mice, Inbred C3H; D017564:Radiation Pneumonitis / Q000188:drug therapy; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014916:Whole-Body Irradiation
D011837:Radiation-Protective Agents; D016222:Fibroblast Growth Factor 2