Evaluation of Doxorubicin vs. Aclarubicin Exposure in C57BL/6J Mice as a Chronic Model of Anthracycline Induced Cardiotoxicity

Abstract

Doxorubicin is an anthracycline chemotherapeutic limited by dose-dependent cardiotoxic effects, while Aclarubicin is a promising alternative anthracycline shown to be less cardiotoxic. Future clinical trials involving Aclarubicin will need to be tested in a relapse setting where patients have already received Doxorubicin. The study’s objective was to evaluate the cardiac effects of Aclarubicin following administration of Doxorubicin and develop a standardized mouse model for assessing cardiotoxicity of oncologic adjuvants after prior Doxorubicin exposure. C57BL/6J mice all received an initial once weekly dose of 5 mg/kg intraperitoneal injections for 4 weeks and rested for an additional 4 weeks. Mice were then administered intraperitoneal injections of one of the following agents once-a-week for 4 weeks: Doxorubicin (5 mg/kg), Aclarubicin (5 mg/kg) or equivalent volumes of saline. Mice were humanely sacrificed after an additional 12-week rest period. Mice that received 40 mg/kg cumulative Doxorubicin had the lowest survival rate and the most weight loss. There were no detectable echocardiographic measurement differences between groups. Overall cardiac changes for all three mice groups were mild via histologic examination by periostin immunohistochemistry, trichrome, and hematoxylin and eosin staining. The results indicate Aclarubicin does not further potentiate Doxorubicin cardiotoxicity.