Relationship between gender and cardiotoxicity from doxorubicin in spontaneously hypertensive rats

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	FDA/CBER	CANCER-11

Authors

• Y Gonzalez-Berrios
• L Chehab
• E Rosen
• J Dickey
• E Herman
• A Rao

Abstract

Treatment of cancer with anthracyclines such as doxorubicin causes dose-limiting cardiotoxicity, particularly in younger females. Dox metabolites generate excess reactive oxygen species (ROS) using an iron-mediated mechanism in mitochondria of cardiac cells. Since cardiomyocytes have lower levels of antioxidant defense, the cardiac cells are sensitive to ROS; however the exact reason for the gender differences in toxicity is unclear. The aim of our study is to understand gender effects in cardiotoxicity. We used female, male, and castrated male adult spontaneously hypertensive rats (SHR). The SHR were implanted with breast cancer cell line derived from SHR. After cell implantation, each group of animals were exposed to either saline, doxorubicin, dexrazoxane, erythropoietin, or combinations with doxorubicin. Testosterone levels were measured to confirm decreased in hormones levels in castrated rats. Tumor size was used as the marker of anticancer activity. Doxorubicin, in combination with either dexrazoxane or erythropoietin showed significant reduction in tumor size in each animal group. In addition, cardiac troponin T levels were used to assess cardiotoxicity and were higher in males treated with Dox than females or castrate males, also treated with Dox. We are currently testing possible mechanistic links between hormone levels, gender-selective toxicity, and oxidant-induced autophagy.

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