A Multifaceted Evaluation of Imatinib-induced Cardiotoxicity in the Rat

Toxicologic Pathology - Tập 39 Số 7 - Trang 1091-1106 - 2011
Eugene H. Herman1, Alan Knapton1, Elliot T. Rosen1, Karol L. Thompson1, Barry A. Rosenzweig1, Joel Estis2, Sara J. Agee2, Quynh-Anh Lu2, John A. Todd2, Steven E. Lipshultz3, Brian B. Hasinoff4, Jun Zhang1
1Food and Drug Administration, Division of Applied Pharmacology Research, Silver Spring, Maryland, USA
2Singulex, Inc., Alameda, California, USA
3University of Miami, Leonard M. Miller School of Medicine, Department of Pediatrics, Mailman Center for Child Development, Miami, Florida, USA
4Faculty of Pharmacy, Apotex Centre, University of Manitoba, Winnipeg, Manitoba, Canada

Tóm tắt

Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric α-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure.

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Toxicologic Pathology

Tập 39 Số 7

1091-1106

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