Myocardial toxicity of arsenic trioxide in a mouse model

Yan Li, Xiuhua Sun, Lipeng Wang, Zhanxiang Zhou, Yujian Kang

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Arsenic trioxide is highly effective in the treatment of acute promyelocytic leukemia (APL). In September 2000, the Trisenox brand of arsenic trioxide for the treatment of relapsed and refractory APL was approved in the United States. A recent clinical report has shown a serious ventricular tachycardia at the therapeutic doses of arsenic trioxide in APL patients. The present study was undertaken to investigate the cardiotoxic effect of arsenic trioxide using a mouse model. Animals were injected intraperitoneally with arsenic trioxide 5 mg/kg/d for 30 d, a dose regiment that has been shown to produce plasma concentrations of arsenic within the range of those present in arsenic-treated APL patients. Analysis of myocardial function revealed that arsenic caused a significant decrease in the maximum rate of rise in intraventricular pressure during ventricular contraction (MAX dP/dt), and significant increases in the end diastolic pressure and ventricle minimum diastolic pressure. In response to β-adrenergic stimulation by isoproterenol, the arsenic-treated heart did not show increase in MAX dP/dt, which was observed as a stress response in the saline-treated controls. The functional alterations were accompanied by cardiomyopathy, as revealed by histopathological and ultrastructural examination. Furthermore, arsenic caused myocardial apoptosis, as determined by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, which was confirmed by caspase-3 activation detected by enzymatic assay. Our study thus demonstrates that arsenic trioxide, in a dose that could produce clinically comparable serum concentrations to those observed in humans, causes cardiotoxicity.

Original languageEnglish (US)
Pages (from-to)63-73
Number of pages11
JournalCardiovascular Toxicology
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

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Toxicity
Arsenic
Acute Promyelocytic Leukemia
Assays
Blood Pressure
DNA Nucleotidylexotransferase
Enzyme Assays
Ventricular Pressure
Ventricular Tachycardia
arsenic trioxide
Cardiomyopathies
Isoproterenol
Caspase 3
Adrenergic Agents
Refractory materials
Labeling
Animals
Therapeutics
Chemical activation
Apoptosis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Toxicology
  • Cardiology and Cardiovascular Medicine

Cite this

Myocardial toxicity of arsenic trioxide in a mouse model. / Li, Yan; Sun, Xiuhua; Wang, Lipeng; Zhou, Zhanxiang; Kang, Yujian.

In: Cardiovascular Toxicology, Vol. 2, No. 1, 01.12.2002, p. 63-73.

Research output: Contribution to journalArticle

Li, Yan ; Sun, Xiuhua ; Wang, Lipeng ; Zhou, Zhanxiang ; Kang, Yujian. / Myocardial toxicity of arsenic trioxide in a mouse model. In: Cardiovascular Toxicology. 2002 ; Vol. 2, No. 1. pp. 63-73.
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