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Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats

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Abstract

Purpose

The antineoplastic anthracycline doxorubicin can induce a dose-dependent cardiomyopathy that limits the total cumulative dose prescribed to cancer patients. In both preclinical and clinical studies, pretreatment with dexrazoxane, an intracellular iron chelator, partially protects against anthracycline-induced cardiomyopathy. To identify potential additional cardioprotective treatment strategies, we investigated early doxorubicin-induced changes in cardiac gene expression.

Methods

Spontaneously hypertensive male rats (n = 47) received weekly intravenous injections of doxorubicin (3 mg/kg) or saline 30 min after pretreatment with dexrazoxane (50 mg/kg) or saline by intraperitoneal injection. Cardiac samples were analyzed 24 h after the first (n = 20), second (n = 13), or third (n = 14) intravenous injection on days 1, 8, or 15 of the study, respectively.

Results

Rats receiving three doses of doxorubicin had minimal myocardial alterations that were attenuated by dexrazoxane. Cardiac expression levels of genes associated with the Nrf2-mediated stress response were increased after a single dose of doxorubicin, but not affected by cardioprotectant pretreatment. In contrast, an early repressive effect of doxorubicin on transcript levels of genes associated with mitochondrial function was attenuated by dexrazoxane pretreatment. Dexrazoxane had little effect on gene expression by itself.

Conclusions

Genomic analysis provided further evidence that mitochondria are the primary target of doxorubicin-induced oxidative damage that leads to cardiomyopathy and the primary site of cardioprotective action by dexrazoxane. Additional strategies that prevent the formation of oxygen radicals by doxorubicin in mitochondria may provide increased cardioprotection.

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Acknowledgments

Affymetrix Inc. provided the microarrays and the loan of equipment to the FDA for the studies in this manuscript. We thank B. Shimada, S. Kassam, D.B. Finkelstein, and J. Lescallet for providing training and assistance with Affymetrix technology.

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Author notes

  1. Jacques Retief

    Present address: Illumina, San Diego, CA, USA

  2. Frank D. Sistare

    Present address: Merck and Co, West Point, PA, USA

Authors and Affiliations

  1. Center for Drug Evaluation and Research, US Food and Drug Administration, LSB64 Room 2036, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA

    Karol L. Thompson

  2. Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA

    Barry A. Rosenzweig, Jun Zhang, Alan D. Knapton, Ronald Honchel, Frank D. Sistare & Eugene H. Herman

  3. Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Steven E. Lipshultz

  4. Affymetrix Inc., Santa Clara, CA, USA

    Jacques Retief

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  1. Karol L. Thompson
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Correspondence to Karol L. Thompson.

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Thompson, K.L., Rosenzweig, B.A., Zhang, J. et al. Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats. Cancer Chemother Pharmacol 66, 303–314 (2010). https://doi.org/10.1007/s00280-009-1164-9

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  • DOI: https://doi.org/10.1007/s00280-009-1164-9

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