Abstract Doxorubicin is a chemotherapeutic drug that causes oxidative stress-mediated cardiotoxicity. To prevent oxidative stress and help to mitigate the cardiotoxic effects of doxorubicin, the iron chelator dexrazoxane is clinically used. However, iron chelators and other antioxidants have not completely succeeded in mitigating this effect and do not protect against iron-independent oxidative damage. One limitation to the development of new cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects the safety and efficacy outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with the SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed two weeks post-implantation. In order to demonstrate the utility of SHR/SST-2 model for monitoring both anticancer efficacy and acute cardiotoxicity, we studied cardiotoxic doxorubicin alone and in combination with dexrazoxane. As predicted, significant tumor reduction, DNA damage, and cardiomyopathy were demonstrated by doxorubicin. Treatment with the cardioprotectant dexrazoxane increased the pro-survival autophagy marker LC3-II and decreased caspase-3 in the heart, as a single agent and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis in tumor and heart. Our results demonstrate the advantage of the immune-proficient SHR/SST-2 model to study anticancer agents and simultaneously address anticancer efficacy and cardiac safety. Citation Format: Yanira Gonzalez-Berrios, Jennifer S. Dickey, Baikuntha P. Aryal, Elliot T. Rosen, Eugene H. Herman, Steven Mog, Asako J. Nakamura, Christophe E. Redon, Ulrich Baxa, Palak Parekh, Karen P. Mason, William Bonner, Ashutosh Rao. Development and application of a syngeneic breast tumor preclinical model to study anticancer efficacy and cardiac safety of doxorubicin and dexrazoxane. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1386. doi:10.1158/1538-7445.AM2013-1386