The role of iron and iron chelators in anthracycline cardiotoxicity.
The redox cycling of anthracyclines promotes the formation of free radicals which are believed to play a central role in their cardiotoxicity. A number of observations indicate that the mechanism of the antineoplastic effect of anthracyclines is independent of their cardiotoxic effect and that it may be possible to prevent toxicity without interfering with therapeutic effect. Iron plays an important role in anthracycline toxicity by promoting the conversion of superoxide into highly toxic hydroxyl radicals through the Haber-Weiss reaction. Conversely, iron deprivation by its high-affinity binding to iron chelating compounds may inhibit anthracycline toxicity by interfering with free radical formation. ICRF-187, a bispiperazonedione which is hydrolyzed intracellularly into a bidentate chelator resembling EDTA, is able to decrease adriamycin-induced free hydroxyl radical formation and to prevent the development of clinical cardiac toxicity in patients receiving long-term anthracycline therapy. Our studies in rat heart cell cultures have shown that iron overload aggravates anthracycline toxicity and that this interaction can be prevented by prior iron chelating treatment. Since iron overload caused by multiple blood transfusions and bone marrow failure is a common condition in patients requiring anthracycline therapy, these observations may have significant clinical implications to the prevention of anthracycline cardiotoxicity.
Hershko
C
C
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
Link
G
G
Tzahor
M
M
Pinson
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000633:toxicity*; D005609:Free Radicals; D006331:Heart Diseases / Q000139:chemically induced*; D006801:Humans; D007501:Iron / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D007502:Iron Chelating Agents; D007501:Iron