Amifostine (ETHYOL) protects rats from mucositis resulting from fractionated or hyperfractionated radiation exposure.
OBJECTIVE
The cytoprotective drug amifostine (Ethyol) protects rats from oral mucositis resulting from a single dose of gamma-irradiation. We expanded earlier studies to determine whether multiple doses of amifostine protect against fractionated or hyperfractionated radiation and whether the active metabolite of amifostine (WR-1065) accumulates in tissues upon repeated administration.


METHODS
Rats received amifostine daily for 5 days in conjunction with a 1-week fractionated radiation schedule and were evaluated for oral mucositis. Rats also received amifostine before the am or pm exposure or b.i.d. in conjunction with hyperfractionated radiation. To determine the pharmacokinetics of WR-1065 after repeated dosing, amifostine was given 5 days a week for 1 or 3 weeks, and rat tissue and plasma were collected at intervals during and after treatment and analyzed for WR-1065.


RESULTS
Amifostine protected rats from mucositis resulting from fractionated or hyperfractionated radiation. When the number of days of amifostine administration was reduced, protection was diminished. A dose of 100 mg/kg given in the morning or 2 doses at 50 mg/kg provided the best protection against hyperfractionated radiation. WR-1065 did not accumulate in tissues or tumor upon repeated administration.


CONCLUSIONS
Amifostine prevented radiation-induced mucositis in a rat model; protection was dose and schedule dependent.
Cassatt
David R
DR
Department of Molecular Biology/Biochemistry, MedImmune Inc. One MedImmune Way, Gaithersburg, MD 20878, USA.
Fazenbaker
Christine A
CA
Bachy
Christine M
CM
Kifle
Gizachew
G
McCarthy
Michael P
MP
D004999:Amifostine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D019583:Dose Fractionation, Radiation; D004353:Drug Evaluation, Preclinical; D005260:Female; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D008624:Mercaptoethylamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D009061:Mouth Mucosa / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013280:Stomatitis / Q000517:prevention & control*; D014018:Tissue Distribution
D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine