Anthracycline toxicity is potentiated by iron and inhibited by deferoxamine: studies in rat heart cells in culture.
The interrelation between iron, iron chelation, and anthracycline toxicity was investigated in a heart cell culture system. Two indicators of cellular damage have been used, lactate dehydrogenase (LDH) release and cell contractility. Both of these indicators have shown a marked increase in doxorubicin toxicity by prior iron loading. This was not a simple additive effect, because at the concentrations used, iron had only a minimal effect on LDH release and no effect at all on contractility, whereas doxorubicin had only a minor effect on contractility. Deferoxamine (DF) treatment of iron-loaded heart cells resulted in a marked decrease in anthracycline toxicity as judged both by LDH leakage and cell contractility. However, DF treatment of normal heart cells had no measurable protective effect against doxorubicin toxicity, whether DF was administered before or simultaneously with doxorubicin. Doxorubicin treatment did not alter cellular malondialdehyde (MDA) concentrations in either normal or iron-loaded cells. Conversely, the protective effect of DF in iron-loaded cells and its failure to prevent anthracycline toxicity in normal cells were both associated with a significant decrease in MDA measurements. Our data indicate that iron overload aggravates anthracycline toxicity and that this interaction may be prevented by effective iron chelating therapy. Because patients requiring anthracycline therapy often have increased tissue iron stores caused by multiple blood transfusions and bone marrow suppression, our observations may have important implications for the prevention of anthracycline toxicity.
Hershko
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Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
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Tzahor
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Kaltwasser
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Athias
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Grynberg
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Pinson
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D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D007501:Iron / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D051381:Rats
D000903:Antibiotics, Antineoplastic; D008315:Malondialdehyde; D004317:Doxorubicin; D007501:Iron; D007770:L-Lactate Dehydrogenase; D003676:Deferoxamine