This study was designed to investigate the mechanism by which (+-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)
propane (ICRF-187) protects against
doxorubicin cardiotoxicity. Others have hypothesized that the major factor contributing to
doxorubicin cardiotoxicity is the depletion of the
antioxidant defense mechanisms of the heart induced by
doxorubicin. Mice were acutely (24-h exposure) or chronically (13-week exposure) treated with
doxorubicin to develop a model for
cardiotoxicity. Five-week-old BALB/c mice were given i.p.
injections of
doxorubicin alone or 30 min after
ICRF-187, while control mice received
ICRF-187 or
0.9% NaCl solution alone without
doxorubicin. Electron microscopy of the mouse hearts demonstrated conclusively that
doxorubicin was cardiotoxic after 13 weeks of exposure, showing mitochondrial degeneration and disruption of the myofibrillar organization. Furthermore, normal morphology of the electron micrographs
after treatment with
doxorubicin and
ICRF-187 indicated that
ICRF-187 was cardioprotective. The activities of the
antioxidants superoxide dismutase,
glutathione peroxidase, and
catalase and the concentration of
reduced glutathione were measured in the heart, liver, kidneys, and skeletal muscle of mice treated with
doxorubicin,
ICRF-187, or the
drug combination. After acute or chronic exposure to the drugs there was no significant difference in
enzyme or
reduced glutathione levels compared to the control mice in any of the treatment groups. It was concluded that neither the cardioprotective effect of
ICRF-187 nor the
cardiotoxicity induced by
doxorubicin was related to an effect on cardiac
antioxidants, but rather another mechanism operated in this particular model.