Key result
The ferrous-ADR-925 complex underwent aerobic oxidation 87 and 44 times slower than the ferrous complexes of EDTA or DAPTA, respectively, but was equally effective in producing spin adducts.
Dexrazoxane's active hydrolysis product ADR-925 protects against doxorubicin cardiotoxicity by complexing iron into a soluble form that is less effective at causing site-specific oxygen radical damage, despite retaining the ability to produce hydroxyl radicals.
May inform dexrazoxane use in anthracycline therapy; animal data leave open human translation.
Dexrazoxane (ICRF-187) is now in clinical use for the prevention of doxorubicin-induced cardiotoxicity. This cardiotoxicity is thought to be due to iron-mediated oxidative stress. Dexrazoxane may be acting through its strongly metal ion binding rings-opened hydrolysis product ADR-925 by complexing iron. Since iron-chelates are known to be able to produce hydroxyl radicals, an electron paramagnetic resonance spin trapping study was undertaken to compare the hydroxyl radical-producing ability of the ferrous-ADR-925 complex with that of the ferrous complexes of ethylenediaminetetraacetic acid (EDTA) and the tetraacid analog of ADR-925 (DAPTA). In spectrophotometric studies it was shown that the ferrous-ADR-925 complex underwent aerobic oxidation 87 and 44 times slower than the ferrous complexes of EDTA or 1,2-diaminopropane-N,N,N',N'-tetraacetic acid (DAPTA), respectively. In spite of the much slower oxidation of the ferrous-ADR-925 complex, it was, nonetheless, equally effective in producing hydrogen peroxide-dependent spin adducts. These spin adducts were produced from the reaction of the spin trap with free hydroxyl radical (HO(.)), and with a transient iron oxidant with HO(.)-like reactivity. Thus, it is concluded that ADR-925 acts by either complexing free iron or iron bound to doxorubicin, and forming a soluble iron complex that is less effective at producing site-specific oxygen radical damage.
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Malisza et al. (1996) studied Doxorubicin-induced cardiotoxicity. Ferrous-ADR-925 complex vs. Ferrous complexes of EDTA and DAPTA was evaluated on Aerobic oxidation rate and hydroxyl radical-producing ability. The ferrous-ADR-925 complex underwent aerobic oxidation 87 and 44 times slower than the ferrous complexes of EDTA or DAPTA, respectively, but was equally effective in producing spin adducts.
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