Role of (+-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) in modulating free radical scavenging enzymes in doxorubicin-induced cardiomyopathy.

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.