Title

Enhanced Doxorubicin Chemotherapy Efficacy in a Carbonyl Reductase 1 Knockout (Cbr1+/-) Mouse Model

Publication Year

2009

Keywords

Doxorubicin, chemotherapy treatment, anti-tumor, anthracycline

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Cancer Biology | Medicine and Health Sciences | Oncology | Preventive Medicine

Abstract

Doxorubicin is one of the most effective anti-tumor anthracycline drugs used today to reduce cancerous tumor proliferation. The efficacy of this drug relies on high circulating concentrations and its metabolism in the body can be disrupted by reducing enzymes into its cardiotoxic and chemotherapeutically less effective metabolite, doxorubicinol. In vivo studies show that carbonyl reductase 1 is the enzyme responsible for the metabolism of doxorubicin. By genetically engineering mice that contain only one copy of the carbonyl reductase 1 gene (Cbr1+/- mice), rduced expression of the enzyme is seen, and less of the parent drug is converted. Transgenic mice containing the polyoma middle T antigen (PyVT) and promoter sequence from the mouse mammary tumor virus (MMTV), which are susceptible to forming tumors in the mammary glands, were bred to C57B16/J and 129SVE Cbr1 knockout mice. The offspring of these matings developed measureable mammary tumors. Upon total tumor volume reaching approximately 200 mm3, the mice were given a chemotherapy treatment of doxorubicin at a dosage of 2 mg/kg for nine consecutive days. During and up to sixteen days after the chemotherapy treatment, mammory tumor volume was measured for data analysis. Tumor regression was analyzed for sex, genotype, and gentic background by the percent change of total tumor volume from the initiation of treatment using the NCSS ver. 2007 and R ver. 2.7.2 statistical software packages. It was determined that mice with only one copy of Cbr1 gene had improved tumor regression and enhanced doxorubicin efficacy as compared to their wild type littermates. Our data show synthesis of a Cbr1 drug inhibitor may increase the power of chemotherapy treatment against cancer proliferation while reducing carditoxic effects.

Department 1 Awarding Honors Status

Biology

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