Title

Latency analysis of tumor formation and of doxorubicin chemotherapy efficacy in mice with differing levels of carbonyl reductase 1 expression

Publication Year

2009

Keywords

Doxorubicin, chemotherapy treatment, tumor growth, doxorubicin efficacy

Disciplines

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

Abstract

Carbonyl reductase 1 (CBR1) is found in all human tissues and serves as an enzyme that reduces carbonyl groups on substrates. Pharmacological substrates, in particular, anthracycline, drugs such as doxorubicin, are effectively reduced by CBR1. This reduction of doxorubicin to doxorubicinol has been linked to decreased efficacy of chemotherapy drugs, as well as to increased cardiotoxic effects. On the other hand, CBR1 has been shown to express characteristics of a tumor suppressor, including decreased metastasis formation. In order to test the effect of CBR1 expression levels on tumor suppression and doxorubicin efficacy, mice with a null allele of CBR1 were bred to PyVT mice in order to generate mice that develop mammary tumors. Latency from birth until first tumor detected was analyzed for Cbr1+/- and Cbr1+/+ mice. Cbr1+/- and Cbr1+/+ mice that underwent doxorubicin treatment were analyzed for latency based on the time needed for the regressed tumor volume to reach greater than or equal to 50% of the tumor volume at initial injection; further analysis examined the time post last injection necessary for tumor volume to reach less than or equal to 100% of the tumor volume at initial injection. Trends seen for tumor growth as a percent of tumor volume at initial injection were also evaluated for Cbr1+/- and Cbr1+/+ mice. After analysis, it was found that Cbr1 expression did not have a significant effect in any examination of latency; differing levels of Cbr1 were not significantly associated with alterations in tumor suppression or doxorubicin efficacy. While this study does not highlight CBR1 as an effective target for pharmaceutical manipulation in order to decrease tumor latency before, during, and after chemotherapy treatment, CBR1 inhibition may reduce cardiotoxic effects of doxorubicin chemotherapy, decreasing the incidence of doxorubicin-induced deaths, without causing a change in tumor growth. Additionally, other factors analyzed in this experiment, such as sex and genetic background, provide insight into the possibility of personalized pharmacogenetic studies which would improve current chemotherapy practices.

Department 1 Awarding Honors Status

Biology

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