title: Narrow amifostine dose windows define radioprotection outcome, following fractionated whole-body irradiation of mice.
abstract: BACKGROUND
  Amifostine is an important broad spectrum cytoprotective agent approved for protection during fractionated radiotherapy. The daily dose of amifostine used, however, is arbitrarily chosen and low compared to the actual tolerable dose.
  
  
  METHODS
  Cohorts of mice (n=6) were treated with one up to 4 consecutive fractions of 6 Gy of whole-body γ-irradiation ((60)Co), supported with increasing daily subcutaneous (s.c.) doses of amifostine (10 mg/g-300 mg/g). Survival and weight loss were monitored. Histopathological analysis was performed in mice receiving 3 × 6 Gy.
  
  
  RESULTS
  By increasing the amifostine dose from 13 to 50 mg and to 160 mg/g, the 50% lethal dose of radiotherapy increased from 2 × 6 Gy to 3 × 6 Gy and to 4 × 6 Gy, respectively. To keep the median weight loss to less than 25% of the initial weight, the dose of amifostine demanded was 23 mg/g, 68 mg/g and 121 mg/g, for 2 × 6 Gy, 3 × 6 Gy and 4 × 6 Gy, respectively. Histopathological analysis revealed a net protection of the liver and intestine of the mice receiving amifostine. Extensive and multiple vacuolar degeneration of the cytoplasm with focal necrosis of hepatocytes and loss of the intestinal villi was the most striking finding in the dying mice treated without amifostine.
  
  
  CONCLUSIONS
  Taking into account the strong association of daily amifostine dose with cytoprotective efficacy and that a slight reduction of the daily amifostine dose can substantially reduce the clinical protective effect during fractionated radiotherapy, it is suggested that randomized trials should be re-appraised adopting amifostine schedules close to the maximum tolerable dose.
authors.affiliation: Department of Radiotherapy - Oncology, Democritus University of Thrace Medical Shool, University General Hospital of Alexandroupolis, Alexandroupolis 68100, Greece.
authors.forename: Christos E
authors.initials: CE
authors.lastname: Zois
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Savvas P
authors.initials: SP
authors.lastname: Tokmakidis
authors.forename: Sotirios
authors.initials: S
authors.lastname: Botaitis
authors.forename: Constantinos
authors.initials: C
authors.lastname: Simopoulos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kortsaris
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
mesh_terms: D004999:Amifostine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D007279:Injections, Subcutaneous; D007422:Intestines / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016019:Survival Analysis; D015431:Weight Loss / Q000187:drug effects / Q000528:radiation effects; D014916:Whole-Body Irradiation
chemical_list: D011837:Radiation-Protective Agents; D004999:Amifostine