Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 2, pp 303–314

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

  • Karol L. Thompson
  • Barry A. Rosenzweig
  • Jun Zhang
  • Alan D. Knapton
  • Ronald Honchel
  • Steven E. Lipshultz
  • Jacques Retief
  • Frank D. Sistare
  • Eugene H. Herman
Original Article

DOI: 10.1007/s00280-009-1164-9

Cite this article as:
Thompson, K.L., Rosenzweig, B.A., Zhang, J. et al. Cancer Chemother Pharmacol (2010) 66: 303. doi:10.1007/s00280-009-1164-9

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.

Keywords

Doxorubicin Anthracycline Cardiotoxicity Microarray Dexrazoxane Cardioprotection 

Copyright information

© US Government 2009

Authors and Affiliations

  • Karol L. Thompson
    • 1
  • Barry A. Rosenzweig
    • 2
  • Jun Zhang
    • 2
  • Alan D. Knapton
    • 2
  • Ronald Honchel
    • 2
  • Steven E. Lipshultz
    • 3
  • Jacques Retief
    • 4
    • 5
  • Frank D. Sistare
    • 2
    • 6
  • Eugene H. Herman
    • 2
  1. 1.Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  2. 2.Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  3. 3.Department of Pediatrics, Leonard M. Miller School of MedicineUniversity of MiamiMiamiUSA
  4. 4.Affymetrix Inc.Santa ClaraUSA
  5. 5.IlluminaSan DiegoUSA
  6. 6.Merck and CoWest PointUSA

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