Myocardial toxicity of arsenic trioxide in a mouse model.
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 B-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.
Department of Medicine, University of Louisville School of Medicine, KY 40202, USA.
Yan
Y
Li
Xiuhua
X
Sun
Lipeng
L
Wang
Zhanxiang
Z
Zhou
Y James
YJ
Kang
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D007124:Immunoenzyme Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010087:Oxides / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D007545:Isoproterenol; D000077237:Arsenic Trioxide