Doxorubicin, an anthracycline drug, is effective against numerous solid and hematological cancers, but cardiotoxicity limits its usefulness. The specific goal of this research project is to determine the potential of two MFH anticancer agents, Didox and Trimidox, to alleviate doxorubicin cardiotoxicity while maintaining or enhancing its anticancer activity. These compounds possess two important properties-potent free radical scavenging and Fe chelating activity-that make them desirable candidates, since doxorubicin cardiotoxicity is believed to be due to a toxic free radical intermediate unrelated to its antitumor activity. Preliminary experiments in two rodent models indicate that MFH's lead compound for cancer treatment protects against anthracycline toxicity in both acute and chronic settings. Furthermore, Didox added to a doxorubicin regimen in leukemia tumor models resulted in enhancement of the antitumor activity. We plan to conduct experiments in the spontaneous hypertensive rat model utilizing varied dosing schedules. To ascertain the protective effect of our agents on doxorubicin-induced cardiotoxicity, we will monitor cardiac function, cardiac enzyme release and histologically examine heart tissue. Also, free radical generation and oxidant injury will be measured by EPR spectroscopy and biochemical assay. Lastly, the impact of the drugs on doxorubicin anticancer activity will be assessed in a mouse breast tumor model. We expect these agents to enhance rather than diminish the antitumor effect. This will lead to improved cancer therapy with less long-term toxicity. PROPOSED COMMERCIAL APPLICATIONS: MFH's anticancer drugs, Didox and Trimidox, are strong free radical scavengers and Fe chelafors, properties which should protect against the cardiotoxicity that limits the usefulness of a widely used anticancerdrugs, the anthracyclines. Data indicate that MFH's drugs enhance the antitumor effect of doxorubicin and not diminish it. A drug with these attributes, if demonstrated, would be a widely used agent in cancer chemotherapy. The potential market for such an agent is more than several hundred million dollars since anthracyclines like doxorubicin are important components of many cancer regimens and have recently been approved for multiple sclerosis.