Doxorubicin has long been used clinically to treat a variety of cancers. Unfortunately, its success is limited due to its cardiotoxic side effects, restricting the cumulative dose that can be given to patients. It is known that the enzyme carbonyl reductase 1 (Cbr1) metabolizes this cancer drug in vivo, leading to the production of its toxic alcohol metabolite, doxorubicinol. A previous study has indicated that decreasing the expression level of carbonyl reductase 1 in male Cbr1+/- mice provided them with significant protection from doxorubicin-induced cardiotoxicity when compared to their wild type littermates. With the intent to identify whether the protection conferred by knocking out one copy of Cbr1 persists in a more diverse population, this subsequent study expanded the previous one to include female mice as well as mice of different genetic backgrounds. It was discovered that the protective effect conferred by a null Cbr1 allele is no longer present, that females significantly longer than males, and that survival is no longer significantly associated with cardiotoxicity. Western blotting, subclinical pathogen analysis, histology, and pedigree analysis were performed in an effort to discover an explanation for the unexpected results. It is believed that alternate acute toxicity such as leukopenia was responsible for mouse death, whereas such factors are controlled in human clinical trials. In the event that decreased Cbr1 levels provide significant cardiac protection, a Cbr1 inhibitor could be created to be taken simultaneously with doxorubicin.
Freeland, M. M. (2009). The Effect of Sex and Background on Doxorubicin-Induced Cardiotoxicity in Carbonyl Reductase 1 +/- Mice: A Comparative Study (Undergraduate honors thesis, University of Redlands). Retrieved from http://inspire.redlands.edu/cas_honors/135