Doxorubicin (Adr),
daunorubicin (Dnr), and analogs of Adr modified in
daunosamine (4'-epi-Adr and 3'-N-acetyl-Adr) were investigated with respect to their reaction with Fe(III) and analyzed for the ability of the corresponding
iron complexes to sustain lipid peroxidation of isolated human platelet membranes. When the proportion of
iron [25 microM Fe(III)] to Adr was 1:4, almost 50% of the
metal was reduced following 1 hour of anaerobic reaction, while only approximately equal to 14% of the bound
iron could be extracted as Fe(II) in the reactions of the Dnr complexes. The reaction of Adr was associated with formation of two main novel
anthracyclines. One of the products had lost the C14 atom of the C9 chain and displayed chromatographic features and visible UV light spectra identical to those of authentic 9-dehydroxyacetyl-9-carboxyl-Adr. In complexes of
iron and Dnr, no significant
anthracycline degradation was observed. Reduction of
anthracycline-bound Fe(III) by 4'-epi-Adr (38%) and 3'-N-acetyl-Adr (21.2%) was consistently less than that by Adr. Complexes of the
anthracyclines investigated had different abilities to sustain lipid peroxidation, which was blocked (a) by the
iron chelators deferoxamine and
bathophenanthroline, indicating that Fe(III) and Fe(II) were needed for the reaction, and (b) by
ICRF-198, the chelating product that forms intracellularly by hydrolysis of
razoxane, which can prevent Adr
cardiotoxicity. Peroxidation was not affected by scavengers of reduced
oxygen radicals (
superoxide dismutase,
catalase, and
mannitol). The isolated membranes contributed to the reduction of
anthracycline-bound Fe(III) and probably represented the main determinant of lipid peroxidation by
iron-Dnr. Lipid peroxidation was significantly less for complexes of
iron with 4'-epi-Adr or 3'-N-acetyl-Adr than for complexes of
iron with Adr. The observed differences may be relevant to the different
biologic properties of Adr and its analogs, in particular their different degrees of
cardiotoxicity.