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 o f the anthracycline cardioprotective agent ICRF-187 [dexrazoxane; (+)- 1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] to remove iron from transfe rrin and ferritin, and copper from ceruloplasmin was examined. ADR-925 completely removed Fe3+ from transferrin at below physiological pH bu t was unreactive at pH 7.4. ADR-925 slowly removed copper from cerulop lasmin at physiological pH (68% removal after 4.8 days). ADR-925 was c apable of removing 18% of the iron from ferritin in 7.0 days. All of t he metalloproteins displayed saturation behavior in their initial rate s of metal ion removal by ADR-925. ICRF-187 may be, in part, preventin g doxorubicin-induced cardiotoxicity by depleting iron and copper from these storage and transport proteins or by scavenging metal ions rele ased from these proteins, thus inhibiting hydroxyl radical production by iron-doxorubicin complexes.