Doxorubicin (DOX) is an important anticancer drug with a wide array of therapeutic uses. Despite its very frequent clinical use, the utility of DOX is severely compromised by dose-limiting cardiotoxicities. While DOX cardiotoxicity has been known for many years, it remains a contemporary problem and therapies to prevent it have not been optimized. The only currently approved therapy (derazoxane) has only modest clinical value and may actually reduce the clinical efficacy of DOX as a tumoricidal agent. We propose to design, test, and optimize novel mechanism-based approaches for prevention of DOX induced cardiac injury and dysfunction that are effective, safe, and relatively cost-efficient. Phase 1 aims include in vitro screening assessments and in vivo pharmacological experiments of nine novel dual acting compounds (new chemical entities) and corresponding two component mixtures for mechanism- based cardioprotection. Studies include cardiomyocyte evaluations (cytoprotection from doxorubicin toxicity, uptake kinetics, cytotoxicities) and formulation strategies (solubilities, stabilities, pH-rate profiles) and pilot studies using relevant mouse models of DOX cardiotoxicity and DOX tumoricidal efficacy
