Abstract 2554: Doxorubicin induced gender differences in tumor-bearing spontaneously hypertensive rats, with an emphasis on cardiotoxicity

Treatment of cancer with anthracyclines such as doxorubicin (Dox) causes dose-limiting cardiotoxicity, particularly in younger females and adult males. However, the exact reason for gender differences in toxicity is unclear. Dox metabolites prompt the generation of excess reactive oxygen species (ROS) using an iron-mediated mechanism in the mitochondria. Cardiomyocytes, in addition to having lower levels of antioxidant enzymes also have higher concentrations of mitochondria and are therefore hypersensitive to ROS. In this study, we investigated the role of gender in Dox induced cardiotoxicity using male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs). The SHRs were implanted with a syngeneic breast cancer cell line previously derived from SHRs. Tumor-bearing SHRs were treated with saline, Dox (10 mg/kg iv), dexrazoxane [(50 mg/kg ip) Drz], or a combination of both Dox and Drz. Tumor size was used to monitor anticancer activity. In all genders, the addition of Dox (alone or in combination with Drz) induced a significant reduction in tumor volume. Addition of Dox (or Dox + Drz) also caused an increase in the heart:body weight ratio for all genders. Histopathological analyses of cardiac sections treated with Dox showed higher heart lesion scores in males than c-males, females, or o-females. We are currently analyzing serum cardiac troponin T, estradiol and testosterone levels for correlation with histopathology. Preliminary findings suggest that sex hormones (estradiol and testosterone) may be influenced by Dox induced cardiotoxicity and may be important in the mode of action of this therapy. After Dox treatment, gene expression analysis of mitochondria-related genes showed increased expression levels in pro-apoptotic genes in both females and, to a greater extent, males. Genes associated with oxidative stress responses also showed a significant increase in male hearts. Our data indicate that adult male SHR hearts were more sensitive to Dox treatment than other genders. Sex hormone levels may influence cardiotoxicity, since Dox treated SHRs for all genders had little to no testosterone or estradiol. Overall, our findings demonstrate Dox induced cardiotoxicity is gender specific and adult males are more cardiosensitive than other genders. The mechanism behind Dox induced cardiotoxicity is currently being elucidated and likely functions, at least in adult male SHRs, through the induction of oxidative stress and expression of apoptotic genes and is inversely correlated to sex hormone levels. Citation Format: Kaytee L. Pokrzywinski, Yanira Gonzalez, Leena M. Chehab, Elliot T. Rosen, Vikrant Vijay, Varsha Desai, Jennifer S. Dickey, V. Ashutosh Rao. Doxorubicin induced gender differences in tumor-bearing spontaneously hypertensive rats, with an emphasis on cardiotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2015-2554