Novel use of zebrafish as a vertebrate model to screen radiation protectors and sensitizers.
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.
McAleer
Mary Frances
MF
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Davidson
Christian
C
Davidson
William Robert
WR
Yentzer
Brad
B
Farber
Steven A
SA
Rodeck
Ulrich
U
Dicker
Adam P
AP
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*
D011799:Quinazolines; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; D020032:Tyrphostins; C101044:RTKI cpd; D004999:Amifostine