Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents.
OBJECTIVE
This study was performed to evaluate the protective benefit of amifostine against esophageal injury from fractionated radiation in a rodent model.


METHODS
Fractionated or sham esophageal irradiation was administered to Fisher-344 rats for 5 consecutive daily fractions of 9 Gy using 150 kV X-rays. Animals received an intraperitoneal injection of amifostine or placebo 30 min before each fraction. Histopathologic analyses for mucosal thickness, submucosal collagen deposition, activation of macrophages, oxidative stress and expression/activation of integrinalphavbeta6 and transforming growth factor (TGF)-beta were performed 5 days and 10 weeks after irradiation.


RESULTS
Pre-RT mean mucosal thickness was 35 microm in both the placebo and the amifostine groups. Five days post-RT, mean mucosal thicknesses were 30 microm in the placebo group versus 37 microm in the amifostine group (p = 0.024). At 10 weeks post-RT, the group receiving amifostine experienced a significant decrease in tunica muscularis damage (p = 0.002), submucosal collagen deposition (p = 0.027), and macrophage accumulation (p = 0.026) when compared with the placebo group. The levels of immunoreactivity for oxidative stress, TGF-beta, and integrinalphavbeta6 were significantly decreased 10 weeks post-RT in the group receiving amifostine treatment compared with placebo group.


CONCLUSIONS
This study demonstrates that amifostine given before each radiation fraction protects against acute and chronic esophageal injury in a rodent model. Protection of the mucosal epithelium integrity by amifostine prevents integrinalphavbeta6 expression which reduces TGF-beta activation and subsequent development of chronic esophageal injury in this model. Further investigation is necessary to determine the clinical relevance of these findings.
Vujaskovic
Zeljko
Z
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Thrasher
Bradley A
BA
Jackson
Isabel L
IL
Brizel
Marla B
MB
Brizel
David M
DM
D000208:Acute Disease; D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001835:Body Weight; D002908:Chronic Disease; D004353:Drug Evaluation, Preclinical; D004947:Esophagus / Q000528:radiation effects*; D005260:Female; D016023:Integrins / Q000378:metabolism; D008262:Macrophage Activation / Q000528:radiation effects; D009092:Mucous Membrane / Q000528:radiation effects; D018384:Oxidative Stress; D011832:Radiation Injuries / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000951:Antigens, Neoplasm; D016023:Integrins; D011837:Radiation-Protective Agents; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D004999:Amifostine