The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925.

The ability of the metal ion binding rings-opened hydrolysis product of the anthracycline cardioprotective agent ICRF-187 [dexrazoxane; (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] to remove iron from transferrin and ferritin, and copper from ceruloplasmin was examined. ADR-925 completely removed Fe3+ from transferrin at below physiological pH but was unreactive at pH 7.4. ADR-925 slowly removed copper from ceruloplasmin at physiological pH (68% removal after 4.8 days). ADR-925 was capable of removing 18% of the iron from ferritin in 7.0 days. All of the metalloproteins displayed saturation behavior in their initial rates of metal ion removal by ADR-925. ICRF-187 may be, in part, preventing doxorubicin-induced cardiotoxicity by depleting iron and copper from these storage and transport proteins or by scavenging metal ions released from these proteins, thus inhibiting hydroxyl radical production by iron-doxorubicin complexes.