title: Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Thrasher
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Jackson
authors.forename: Marla B
authors.initials: MB
authors.lastname: Brizel
authors.forename: David M
authors.initials: DM
authors.lastname: Brizel
mesh_terms: 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
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D011837:Radiation-Protective Agents; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D004999:Amifostine