Enhancement of adriamycin toxicity by iron chelates is not a free radical mechanism.
The possible involvement of metal ions and free radicals in the cytotoxic mechanism of Adriamycin (ADR) was investigated, using a model system of Escherichia coli cells. It is shown that E. coli mediated the production of free radicals under anaerobic (ADR-semiquinone) and aerobic (superoxide) conditions. ADR-induced loss of colony-forming ability was enhanced by the addition of iron (Fe) chelates. These observations suggested that a Fenton-type free radical mechanism was responsible for ADR toxicity. However, the mortality rate was essentially unchanged by the exclusion of oxygen. It was also unaffected by the addition of H2O2, catalase, or chelating agents. Cu(II), Zn(II) or Mg(II) had no effect on ADR toxicity. ADR and iron chelates did not induce measurable amounts of DNA strand-breaks. These observations suggest a mechanism of ADR-induced cell killing that is enhanced by Fe chelates, but does not directly involve oxygen-derived free radicals.
Gelvan
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Dept. of Human Nutrition and Metabolism, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
D000693:Anaerobiosis / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000633:toxicity*; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects; D005609:Free Radicals / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*
D002614:Chelating Agents; D005609:Free Radicals; D007502:Iron Chelating Agents; C024703:adriamycin semiquinone radicals; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase