Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the treatment of breast cancer, sarcoma, and pediatric leukemia. Of the two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b), which is involved in DNA transcription, but not DNA replication. Long-term cancer survivors who were treated with doxorubicin and other anthracyclines often suffer from dose-dependent cardiotoxicity. Laboratory data showed that Top2a mediates doxorubicin?s tumoricidal activity, whereas Top2b mediates doxorubicin?s cardiotoxic effect. At present, dexrazoxane is the only FDA approved drug for cardio-protection. The cardio-protective effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b to inhibit Top2b?s catalytic cycle. Currently, dexrazoxane is given concurrently with doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere with doxorubicin?s tumoricidal effect. However, subclinical doxorubicin-induced cardiotoxicity is known to occur much earlier, perhaps at the initiation of doxorubicin therapy. Thus, dexrazoxane has limited clinical utility as specified by FDA?s approved indication. In preliminary studies, dexrazoxane induced an ubiquitin/ proteasome- mediated degradation of Top2b, but not Top2a. By administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre-treatment eight hours before doxorubicin provided complete protection against doxorubicin-induced cardiotoxicity in an animal model. In this proposal, this novel strategy will be tested in breast cancer patients prescribed doxorubicin- containing regimens.
Two specific aims will be studied.
Aim 1 : To determine whether dexrazoxane given at a lower than FDA-approved dose is effective in degrading Top2b and the time-course of Top2b degradation in human volunteers.
Aim 2 : To test a mechanism-based hypothesis that early administration of dexrazoxane prevents doxorubicin-induced cardiotoxicity in non-metastatic, HER2- negative female breast cancer patients. HER2-negative, stage I-III female breast cancer patients will be enrolled in this prospective randomized, placebo-controlled, double-blind study. Patients will be monitored by cardiac MRI, Top2a, Top2b, and biomarkers before and after dexrazoxane/doxorubicin therapy. Tumor regression will be followed by oncologists clinically. Overall survival, event-free survival, and overall response (using response evaluation criteria in solid tumors -RECIST) will be collected to compare outcomes of cancer therapy with or without pre-treatment of dexrazoxane. Successful implementation of these trials will provide a novel and cost-effective strategy to prevent doxorubicin-induced cardiotoxicity.

Public Health Relevance

Cancer patients who have had long-term treatment with the drug doxorubicin often suffer from cardiotoxicity, caused by an enzyme, topoisomerase 2b (Top2b), which can be prevented by dexrazoxane, an FDA- approved drug that inhibits Top2b. However, dexrazoxane is not commonly used due to a concern for reducing the effectiveness of doxorubicin. This study will test a new strategy to resurrect the clinical use of dexrazoxane by giving it to patients eight hours before doxorubicin based on a different mechanism of action by dexrazoxane.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Desvigne-Nickens, Patrice
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University of Missouri-Columbia
Internal Medicine/Medicine
Schools of Medicine
United States
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