Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats.
OBJECTIVE
To compare the protective effects of amifostine and dexrazoxane against the chronic toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR).


METHODS
The animals were pretreated with amifostine (200 mg/kg. i.p.), dexrazoxane (25 mg/kg, i.p.) or saline 30 min before the administration of doxorubicin (1 mg/kg, i.v.), once-weekly for 12 weeks. Control animals received similar amounts of amifostine or saline. The SHR underwent necropsy examination 1 week after the last dosing, and cardiac, renal, and gastrointestinal lesions were graded semiquantitatively.


RESULTS
Amifostine and dexrazoxane provided equal degrees of protection against the renal toxicity of doxorubicin. However, dexrazoxane was more cardioprotective than amifostine, and prevented the mortality induced by doxorubicin. This mortality was not decreased by pretreatment with amifostine. The loss of body weight caused by doxorubicin was actually worsened by coadministration of amifostine.


CONCLUSIONS
Compared to dexrazoxane, amifostine provided a comparable degree of protection against the nephrotoxicity of doxorubicin, but was less cardioprotective and did not prevent the mortality and loss of body weight produced by doxorubicin. These differences may be related to the fact that amifostine may act as a scavenger of reactive oxygen species, whereas dexrazoxane may prevent their formation.
Herman
E H
EH
Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708, USA.
Zhang
J
J
Chadwick
D P
DP
Ferrans
V J
VJ
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D009206:Myocardium / Q000473:pathology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011837:Radiation-Protective Agents; D011929:Razoxane; D004317:Doxorubicin; D004999:Amifostine