title: Novel use of zebrafish as a vertebrate model to screen radiation protectors and sensitizers.
abstract: OBJECTIVE
  Zebrafish (Danio rerio) embryos provide a unique vertebrate model to screen therapeutic agents easily and rapidly because of their relatively close genetic relationship to humans, ready abundance and accessibility, short embryonal development, and optical clarity. To validate zebrafish embryos as a screen for radiation modifiers, we evaluated the effects of ionizing radiation in combination with a known radioprotector (free radical scavenger Amifostine) or radiosensitizing agent (tyrosine kinase inhibitor AG1478).
  
  
  METHODS
  Viable zebrafish embryos were exposed to 0-10 Gy single-fraction 250 kVp X-rays with or without either Amifostine (0-4 mM) or AG1478 (0-10 microM) at defined developmental stages from 1-24 h postfertilization (hpf). Embryos were examined for morphologic abnormalities and viability until 144 hpf.
  
  
  RESULTS
  Radiation alone produced a time- and dose-dependent perturbation of normal embryonic development and survival with maximal sensitivity at doses > or =4 Gy delivered before 4 hpf. Amifostine markedly attenuated this effect, whereas AG1478 enhanced teratogenicity and lethality, particularly at therapeutically relevant (2-6 Gy) radiation doses.
  
  
  CONCLUSIONS
  Collectively, these data validate the use of zebrafish as a vertebrate model to assess the effect of radiation alone or with radiation response modulators. Zebrafish embryos may thus provide a rapid, facile system to screen novel agents ultimately intended for human use in the context of therapeutic or accidental radiation exposure.
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McAleer
authors.forename: Christian
authors.initials: C
authors.lastname: Davidson
authors.forename: William Robert
authors.initials: WR
authors.lastname: Davidson
authors.forename: Brad
authors.initials: B
authors.lastname: Yentzer
authors.forename: Steven A
authors.initials: SA
authors.lastname: Farber
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rodeck
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D004625:Embryo, Nonmammalian / Q000528:radiation effects; D023421:Models, Animal; D011799:Quinazolines; D011833:Radiation Injuries, Experimental / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D016019:Survival Analysis; D020032:Tyrphostins / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D011799:Quinazolines; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D020032:Tyrphostins; C101044:RTKI cpd; D004999:Amifostine