title: Doxorubicin reduces the iron(III) complexes of the hydrolysis products of the antioxidant cardioprotective agent dexrazoxane (ICRF-187) and produces hydroxyl radicals.
abstract: Dexrazoxane (ICRF-187) is very effective in protecting against doxorubicin-induced cardiotoxicity. Dexrazoxane likely acts though its metal ion binding hydrolysis product ADR-925 by reducing doxorubicin-promoted iron-based oxygen-free radical damage. In this study we show that doxorubicin and epirubicin (but not daunorubicin, idarubicin, or mitoxantrone) are able to reduce iron(III)-ADR-925 and under aerobic conditions are able to produce hydroxyl radicals that are detectable by EPR spin trapping. The ability of iron(III)-ADR-925 to produce hydroxyl radicals in the presence of anthraquinones is compared with that of other ferric chelates, including those of the one-ring open hydrolysis intermediates of dexrazoxane, the tetraacid derivative of ADR-925, EDTA, DTPA, and deferoxamine. The anthraquinones that lacked an alpha-ketol side chain (daunorubicin, idarubicin, and mitoxantrone) produced much less hydroxyl radical than those that did (doxorubicin and epirubicin). The model alpha-ketol, dihydroxyacetone, was also able to promote the formation of hydroxyl radicals in the presence of iron(III) chelates. Since dexrazoxane and doxorubicin are administered together, the possibility must be considered that anthracyclines with alpha-ketol side chains may be oxidized by iron(III)-ADR-925, thus changing their antitumor activity.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Malisza
authors.forename: B B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D000332:Aerobiosis; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005029:Ethylenediamines / Q000737:chemistry*; D005290:Ferric Compounds / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006321:Heart / Q000187:drug effects; D006868:Hydrolysis; D017665:Hydroxyl Radical; D008942:Mitoxantrone / Q000737:chemistry; D008956:Models, Chemical; D010084:Oxidation-Reduction; D011929:Razoxane / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D002614:Chelating Agents; D005029:Ethylenediamines; D005290:Ferric Compounds; D005296:Ferrous Compounds; D017665:Hydroxyl Radical; D011929:Razoxane; C059866:ICRF 198; D004317:Doxorubicin; D008942:Mitoxantrone; D005998:Glycine