Cancer Chemotherapy and Pharmacology

, Volume 48, Issue 4, pp 297–304

The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity

  • Eugene H. Herman
  • Jun Zhang
  • Nader Rifai
  • Steven E. Lipshultz
  • Brian B. Hasinoff
  • Douglas P. Chadwick
  • Alan Knapton
  • Jonathan Chai
  • Victor J. Ferrans
Original Article
  • 195 Downloads

Abstract.

Purpose: To compare the protective effect of dexrazoxane (DRZ) against cardiotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX). Methods: Adult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DXR (i.v.) or 0.5 mg/kg MTX (i.v.), either alone or 30 min after 25 mg/kg DRZ (i.p.) weekly for up to 12 weeks. Animals treated with DXR alone either died (n=2) or were killed (n=3) at a cumulative dose of 10 mg/kg. The severity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3. Results: Cardiac lesions were observed in all SHR given DXR or MTX alone, and were attenuated in those given DRZ prior to either DXR (mean lesion scores 2.7 vs 1.5; P<0.05) or MTX (mean lesion scores 2.0 vs 1.25; P<0.05). Cardioprotection was also demonstrated by monitoring serum levels of cardiac troponin T (cTnT), which were elevated in all animals receiving DXR or MTX alone. These elevations were attenuated in SHR given the combination of DXR and DRZ (mean values 0.79 ng/ml vs 0.24 ng/ml; P<0.05) and MTX and DRZ (mean values 0.19 ng/ml vs 0.04 ng/ml; P<0.05). Biochemical studies have shown that both DXR and MTX form potentially cardiotoxic complexes with iron. ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA, diethylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR. Conclusions: The present study showed that DRZ significantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of cardiac tissues and by monitoring the concentrations of cTnT in serum.

Doxorubicin Mitoxantrone Dexrazoxane Cardiotoxicity Cardiac troponin T 

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Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Eugene H. Herman
    • 1
  • Jun Zhang
    • 1
  • Nader Rifai
    • 2
  • Steven E. Lipshultz
    • 3
  • Brian B. Hasinoff
    • 4
  • Douglas P. Chadwick
    • 1
  • Alan Knapton
    • 1
  • Jonathan Chai
    • 5
  • Victor J. Ferrans
    • 5
  1. 1.Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, 8301 Muirkirk Road, Laurel, MD 20708, USA
  2. 2.Department of Laboratory Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  3. 3.Division of Pediatric Cardiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, USA
  4. 4.Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba R3T2N2, Canada
  5. 5.Pathology Section, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA

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