The hydrolysis product of ICRF-187 promotes iron-catalysed hydroxyl radical production via the Fenton reaction

Abstract

d-1,2-Bis(3,5-dioxopiperazine-1-yl)propane (ICRF-187) (ADR-529) is a drug that ameliorates the cardiotoxicity of Adriamycin®. The drug enters cells where hydrolysis leads to its diacid diamide product, dl- N, N′-dicarboxamidomethyl- N, N′-dicarboxymethyl-1,2-diaminopropane (ICRF-198) (ADR-925), which is structurally similar to ethylenediaminetetraacetic acid (EDTA). The protective mechanism of ICRF-187 is unknown, but a plausible explanation is that ICRF-198 chelates iron intracellularly to prevent iron-dependent free radical reactions such as hydroxyl radical (OH) production. We have compared Fe(ICRF-198) with Fe(EDTA) in its ability to promote OH formation in several Fenton reaction systems. The Fenton reaction was studied with H 2O 2; and Fe 2+ chelates or catalytic amounts of the iron chelates in the presence of Adriamycin radicals, paraquat radicals, superoxide anion radicals (O − 2), and ascorbate as reducing species. OH was detected with deoxyribose and dimethyl sulfoxide. The two methods gave comparable results. Fe(ICRF-198) was 80–100% as effective as Fe(EDTA) at promoting OH production in the presence of the organic radicals and ascorbate, 30–70% in the presence of O − 2, and 150% with non-cycling Fe 2+. Fe(EDTA) is a more efficient catalyst of OH production than physiological chelates such as ADP, ATP and citrate. Therefore, by comparing previous work which examined physiological chelates and Fe(EDTA) with the present work, Fe(ICRF-198) appears to be a better OH catalyst than the physiological chelates. These results suggest that ICRF-198 generated in vivo from ICRF-187 would not protect against intracellular OH production. They also imply that OH production may not be as important in Adriamycin cardiotoxicity as other radical reactions, such as lipid peroxidation and thiol oxidation, that are inhibited by ICRF-198.