C. Thomas et al., THE HYDROLYSIS PRODUCT OF ICRF-187 PROMOTES IRON-CATALYZED HYDROXYL RADICAL PRODUCTION VIA THE FENTON REACTION, Biochemical pharmacology, 45(10), 1993, pp. 1967-1972
d-1,2-Bis(3,5-dioxopiperazine-1-yl)propane (ICR.F-187) (ADR-529) is a
drug that ameliorates the cardiotoxicity of Adriamycin(R). The drug en
ters cells where hydrolysis leads to its diacid diamide product, midom
ethyl-N,N'-dicarboxymethyl-1,2-diaminopropane (ICRF-198) (ADR-925), wh
ich is structurally similar to ethylenediaminetetraacetic acid (EDTA).
The protective mechanism of ICRF-187 is unknown, but a plausible expl
anation is that ICRF-198 chelates iron intracellularly to prevent iron
-dependent free radical reactions such as hydroxyl radical (.OH) produ
ction. We have compared Fe(ICRF-198) with Fe(EDTA) in its ability to p
romote .OH formation in several Fenton reaction systems. The Fenton re
action was studied with H2O2 and Fe2+ chelates or catalytic amounts of
the iron chelates in the presence of Adriamycin radicals, paraquat ra
dicals, superoxide anion radicals (O2-), and ascorbate as reducing spe
cies. .OH was detected with deoxyribose and dimethyl sulfoxide. The tw
o methods gave comparable results. Fe(ICRF-198) was 80-100% as effecti
ve as Fe(EDTA) at promoting .OH production in the presence of the orga
nic radicals and ascorbate, 30-70% in the presence of O2-, and 150% wi
th non-cycling Fe2+. Fe(EDTA) is a more efficient catalyst of .OH prod
uction than physiological chelates such as ADP, ATP and citrate. There
fore, by comparing previous work which examined physiological chelates
and Fe(EDTA) with the present work, Fe(ICRF-198) appears to be a bett
er .OH catalyst than the physiological chelates. These results suggest
that ICRF-198 generated in vivo from ICRF-187 would not protect again
st intracellular .OH production. They also imply that .OH production m
ay not be as important in Adriamycin cardiotoxicity as other radical r
eactions, such as lipid peroxidation and thiol oxidation, that are inh
ibited by ICRF-198.