title: Radiation-induced craniofacial bone growth inhibition: acute and long-term effects on bone histopathology with and without cytoprotection.
abstract: BACKGROUND
  The authors previously established an animal model of radiation-induced craniofacial bone growth inhibition and demonstrated the effectiveness of cytoprotection in preserving growth using amifostine, but the mechanism is unclear. The objective of this study was to investigate the acute and long-term histopathologic effects of single-dose orthovoltage irradiation on craniofacial bone with and without cytoprotection.
  
  
  METHODS
  Sixty infant New Zealand White rabbits (7-week-old) were randomized into three groups (n = 20 per group): group 1, 0-Gy, sham irradiation; group 2, 35-Gy single-dose orthovoltage irradiation; and group 3, cytoprotection with amifostine before irradiation. Orbitozygomatic complex bone was harvested from animals 12 hours after irradiation and at skeletal maturity (21 weeks of age). Histologic parameters measured included native bone cell (osteoblast, osteoclast, and osteocyte) populations, periosteal proliferation indices (MIB-1 stains), bone turnover rates [triple fluorochromes: tetracycline administered at 7 weeks of age (before irradiation), alizarin complexone at 12 weeks, and calcein at 16 weeks of age], and endosteal space fibrosis levels.
  
  
  RESULTS
  Orthovoltage irradiation significantly (p < 0.05) reduced osteoblast and osteoclast counts 12 hours after irradiation (age, 7 weeks) with or without pretreatment with amifostine but had no effect on osteocyte populations. Long-term analysis at age 21 weeks demonstrated significantly (p < 0.05) increased osteoblast counts, reduced endosteal space fibrosis, reduced periosteal proliferation indices, and improved bone turnover (fluorochrome stains) in amifostine-treated animals.
  
  
  CONCLUSIONS
  This study suggests that amifostine cytoprotection is mediated through a combination of reduced cellular injury with enhanced promotion of cellular bone rebuilding potential.
authors.affiliation: Toronto, Ontario, Canada; Geneva, Switzerland; and Seattle, Wash. From the Division of Plastic Surgery, The Hospital for Sick Children Center for Craniofacial Care and Research, The Hospital for Sick Children Research Institute, University of Toronto, the Department of Pathology, Mount Sinai Hospital, the Department of Clinical Physics, Ontario Cancer Institute, Princess Margaret Hospital, the Pediatric Surgery Clinic, University of Geneva Children's Hospital, and the Department of Surgery, Center for Reconstructive Surgery, University of Washington.
authors.forename: David A
authors.initials: DA
authors.lastname: O'Donovan
authors.forename: Giorgio C
authors.initials: GC
authors.lastname: La Scala
authors.forename: Iona
authors.initials: I
authors.lastname: Leong
authors.forename: Maria
authors.initials: M
authors.lastname: Mendes
authors.forename: Marianne
authors.initials: M
authors.lastname: Rogers
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Pritzker
authors.forename: Ivan
authors.initials: I
authors.lastname: Yeung
authors.forename: Cho Y
authors.initials: CY
authors.lastname: Pang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Neligan
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Forrest
mesh_terms: D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D016723:Bone Remodeling; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D009915:Orbit / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology / Q000528:radiation effects*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D010521:Periosteum / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015050:Zygoma / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology / Q000528:radiation effects*
chemical_list: D019394:Ki-67 Antigen; D011837:Radiation-Protective Agents; D004999:Amifostine