Anthracyclines such as doxorubicin and daunorubicin are valuable anti- cancer drugs but their clinical utility is compromised by cumulative dose-dependent by a cumulative dose dependent cardiotoxicity. Anthracycline cardiotoxicity has been linked to free radical damage via mechanisms that involve disruption of iron regulation and formation of superoxide anion. Although the quinone moiety of anthracyclines has been known for two decades to redox cycle and form superoxide anion, only recently has the C-13 hydroxyl anthracycline metabolites been reported to interfere with iron regulation by irreversibly inhibiting iron regulatory protein (IRP-1) and cytosolic aconitase. This proposal is designed to utilize this information by determining he cardiac effects of doxorubicin analogs that do not form C-13 hydroxymetabolites (GPX- 100 and GPX-150) or redox cycle via quinone mechanisms (GPX-150). Echocardiography, histopathology scoring, papillary muscle function, [3H] ryanodine binding to sarcoplasmic reticulum, and plasma troponin I levels will e used to evaluate cardiac toxicity in rabbits chronically treated doxorubicin, GPX-100 and GPX-150. Anti-neoplastic activity of each anthracycline will be assessed by evaluating median survival in an in vivo P388 model of murine leukemia. This study will test the C-13 hydroxy metabolites and quinone redox hypothesis of anthracycline cardiotoxicity and provide important insights into determining the potential for commercialization of these two novel doxorubicin analogs.
A novel doxorubicin analog devoid of cardiotoxicity but with an anti- tumor spectrum of activity and efficacy similar to doxorubicin, would be expected to be used extensively in treatment of leukemias, lymphomas, breast cancer, and solid tumors. Such an analog could e expected to eventually replace doxorubicin in chemotherapeutic regimens.
