Amifostine induces antioxidant enzymatic activities in normal tissues and a transplantable tumor that can affect radiation response.
OBJECTIVE
To determine whether amifostine can induce elevated manganese superoxide dismutase (SOD2) in murine tissues and a transplantable SA-NH tumor, resulting in a delayed tumor cell radioprotective effect.


METHODS
SA-NH tumor-bearing C3H mice were treated with a single 400 mg/kg or three daily 50 mg/kg doses of amifostine administered intraperitoneally. At selected time intervals after the last injection, the heart, liver, lung, pancreas, small intestine, spleen, and SA-NH tumor were removed and analyzed for SOD2, catalase, and glutathione peroxidase (GPx) enzymatic activity. The effect of elevated SOD2 enzymatic activity on the radiation response of SA-NH cells was determined.


RESULTS
SOD2 activity was significantly elevated in selected tissues and a tumor 24 h after amifostine treatment. Catalase and GPx activities remained unchanged except for significant elevations in the spleen. GPx was also elevated in the pancreas. SA-NH tumor cells exhibited a twofold elevation in SOD2 activity and a 27% elevation in radiation resistance. Amifostine administered in three daily fractions of 50 mg/kg each also resulted in significant elevations of these antioxidant enzymes.


CONCLUSIONS
Amifostine can induce a delayed radioprotective effect that correlates with elevated levels of SOD2 activity in SA-NH tumor. If limited to normal tissues, this delayed radioprotective effect offers an additional potential for overall radiation protection. However, amifostine-induced elevation of SOD2 activity in tumors could have an unanticipated deleterious effect on tumor responses to fractionated radiation therapy, given that the radioprotector is administered daily just before each 2-Gy fractionated dose.
Grdina
David J
DJ
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA. dgrdina@uchicago.edu
Murley
Jeffrey S
JS
Kataoka
Yasushi
Y
Baker
Kenneth L
KL
Kunnavakkam
Rangesh
R
Coleman
Mitchell C
MC
Spitz
Douglas R
DR
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D002374:Catalase / Q000378:metabolism*; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008624:Mercaptoethylamines / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009206:Myocardium / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000201:enzymology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
D004999:Amifostine; D002374:Catalase; D005979:Glutathione Peroxidase; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane