Anthracycline Specificities of Carbonyl Reductases

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DESCRIPTION (provided by applicant): Anthracyclines, such as doxorubicin and daunorubicin, are a family of drugs commonly used to treat cancer. Though anthracyclines are potent anti-tumor drugs, their use is limited, as they also are known to be toxic to the heart and have the potential to cause congestive heart failure in many of the patients. There is accumulating evidence that the toxic effects on the heart are largely attributable to an anthracycline metabolite that is formed and retained in cardiac cells. The conversion of the anthracyclines to their cardiotoxic metabolites is catalyzed by carbonyl reductase. Preliminary studies with rabbit heart have uncovered several different carbonyl reductases, each with different catalytic efficiencies for daunorubicin and doxorubicin. This important finding may help explain why, in anthracycline cardiotoxicity studies (using doxorubicin) performed with rabbits, only 50 percent of the rabbits developed cardiotoxicity. It is hypothesized that the rabbits with high sensitivity to the doxorubicin possessed a complement of enzymes that had good activity on doxorubicin, while those that did not develop cardiotoxicity did not possess such enzymes. More work is needed to further test this hypothesis. The specific aims of this project focus on the purification (Specific Aim 1) and kinetic analysis (Specific Aim 2) of the enzymes with anthracycline reductase activity present in rabbit heart. This project will be a prelude to future studies aimed at correlating the distribution of anthracycline reductases with resistance (or susceptibility) to cardiotoxicity. The long-term goal of this study is to be able to develop a rabbit model for predicting likelihood of cardiotoxicity as a function of the anthracycline reductases that the rabbits possess. Ultimately such a model could be extended to humans, and as a result, patients could be assessed for risk of developing cardiotoxicity by determining the complement of anthracycline reductases that they possess. The information from this proposal may be used to improve the use of anthracyclines in the treatment of cancer by leading to treatments that greatly reduce the threat of heart damage.