Title

Effect of CBR1 on Chemotherapy Drug Metabolism: A Paclitaxel Control Study

Publication Year

2007

Keywords

CBR1, chemotherapy, metabolism, doxorubicin

Disciplines

Cancer Biology | Medicine and Health Sciences | Oncology | Preventive Medicine

Abstract

Doxorubicin is a chemotherapy drug shown to provide antitumor activity against solid and nonsolid tumors. Like other anthracyclines, heart damage often occurs with treatment. While the exact mechanism of this cardiotoxicity is unknown, recent research has found that the catalytic activity of an enzyme called carbonyl reductase 1 (Cbr1) is largely responsible due to its reduction of doxorubicin to its alcohol metabolite, doxorubicinol, thought to be the cardiotoxin. Evidence shows that doxorubicinol is less potent in tumor growth inhibition than doxorubicin. A knockout mouse was created to contain a null allele for the carbonyl reductase 1 gene, and was found to be protected against heart muscle damage. Therefore, tratment with doxorubicin in Cbr1 knockout mice should exhibit an enhanced drug efficacy, due to the lower amount of doxorubicinol formation. To test this hypothesis, Cbr1 knockout mice with the PyVT oncogene were bred to induce mammary tumors, and were used in a 29 day treatment protocol to assess drug efficacy by measuring tumor regression. To provide a control for this experiment, similarly bred mice were subjected to an identical 29 day study in which mice were treated with paclitaxel. Paclitaxel inhibits tumor growth by microtubule inhibition, and is not known to be metabolized by carbonyl reductase 1. Ten mice with the appropriate genotypes have been confirmed and are being monitored for tumor development. Two of these mice have been treated with paclitaxel. The treatment protocol is currently being performed, and has been partially completed for two mice. These preliminary data appear to show no difference in efficacy between knockout and wild type mice, but more data is needed for statistical analysis. This study should provide evidence that inhibition of the carbonyl reductase 1 enzyme in humans will increase the efficacy of doxorubicin.

Department 1 Awarding Honors Status

Biology

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