Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats.
Since the iron-mediated formation of free radicals is considered to be a critical factor in the pathogenesis of the toxicity of doxorubicin (DXR), comparisons were made of the protective effects of two iron chelators, ICRF-187 and desferrioxamine (DFO), against the chronic cardiac and renal toxicity induced by DXR in spontaneously hypertensive rats (SHR). Two preparations of DFO were studied: DFO mesylate (DFO-M) and a polymeric form (DFO-P) in which DFO is conjugated to hydroxyethyl starch. Groups of 5 SHR each were given 12 weekly i.v. injections of 1 mg/kg DXR either alone or 30 min after the i.p. injection of 25 mg/kg ICRF-187, 50 mg/kg DFO-M, 50 mg/kg DFO-P, or 100 mg/kg DFO-P. A semiquantitative assessment was made of the cardiomyopathy (Billingham scale) and nephropathy. Renal protection was minimal with DFO-M and moderate with ICRF-187 and both doses of DFO-P. There was no cardiac protection with DFO-M. Both doses of DFO-P provided similar but modest degrees of cardiac protection. DXR-induced mortality was not prevented by either preparation of DFO. ICRF-187 provided a higher degree of protection against the cardiotoxicity and the mortality induced by DXR. Since both DFO and ICRF-187 are highly efficient chelators of iron in vitro, the differences in their in vivo protective effects are thought to be related to their cellular uptake and intracellular distribution and to the relative availability of different intracellular iron pools to these agents.
Herman
E H
EH
Division of Research and Testing, Food and Drug Administration (HFD-472), Laurel, MD 20708.
Zhang
J
J
Ferrans
V J
VJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003676:Deferoxamine / Q000627:therapeutic use*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000627:therapeutic use*
D011929:Razoxane; D004317:Doxorubicin; D003676:Deferoxamine