Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model.

In this study doxorubicin, epirubicin, and mitoxantrone were compared for their cardiotoxic potential in a chronic mouse model in an effort to identify and compare their mechanism(s) of toxicity. In addition, the cardioprotective ability of ICRF-187 [(+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] with each anticancer drug was evaluated in this model. The antioxidant capacity (superoxide dismutase, reduced glutathione, catalase, and glutathione peroxidase) was assessed following drug treatment. Five-week-old BALB/c mice received weekly i.p. injections of each drug or the drug and ICRF-187 over a 3-month period. ICRF-187 was administered 30 min prior to the anticancer drug. The hearts were examined by electron and light microscopy to assess subcellular changes, and the cardiac and hepatic antioxidant levels were measured concurrently. Chronic treatment with these drugs or each combined with ICRF-187 did not change the antioxidant levels relative to the control values. However, all three drugs caused cardiac damage during chronic exposure. Both epirubicin and mitoxantrone caused less severe damage than doxorubicin, and epirubicin was the least cardiotoxic of the three. ICRF-187 was cardioprotective for epirubicin and doxorubicin but not for mitoxantrone. These results suggest epirubicin acts by a mechanism similar to that of doxorubicin that is probably mediated by oxygen-free radicals, while mitoxantrone acts by a different mechanism to cause cardiotoxicity.

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.

Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529).

Anthracyclines are powerful anticancer drugs whose use is limited by the development of chronic cardiotoxicity. The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans. It does this without effecting either the acute toxicities or the anticancer activity. Therefore, with a specific antagonist, the mechanism of activity of the anthracyclines can be explored. This review discusses recent clinical trials and animal models addressing this issue and concludes by hypothesizing a mechanism of action.