doi: 10.1161/CIRCULATIONAHA.108.776831
(Circulation. 2008;118:84-95.)
© 2008 American Heart Association, Inc.
Basic Science for Clinicians |
Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics
From the Cardiology Department, Children’s Hospital Boston, Boston, Mass (M.H.C.); Department of Medicine, Divisions of Cardiology and Women’s Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.H.C.); Center for Translational Medicine and Cardiology Division, Jefferson Medical College, Philadelphia, Pa (R.K., T.F.); and Program in Cell and Developmental Biology, Jefferson College of Graduate Studies, Philadelphia, Pa (T.F.).
Correspondence to Thomas Force, MD, Center for Translational Medicine, College Building, Room 316, 1025 Walnut St, Philadelphia, PA 19107. E-mail thomas.force@jefferson.edu
Key Words: cardiomyopathy • drugs • heart failure • receptors
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Introduction |
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Treatment of patients with cancer has changed radically over the last several years with the advent of "targeted therapeutics." Whereas traditional chemotherapy was directed at all rapidly dividing cells, whether cancerous or not, today’s anticancer drugs are increasingly tailored to the specific genetics of each cancer. This targeted approach, predominantly via inhibition of tyrosine kinase activity, has markedly improved the management of cancers including chronic myeloid leukemia (CML), breast cancer, gastrointestinal stromal tumor (GIST), renal cell carcinoma (RCC), and colon carcinoma.1–5
Inhibitors of tyrosine kinases are of 2 classes: monoclonal antibodies (mAbs), typically targeting growth factor receptor tyrosine kinases, and small molecules, referred to as tyrosine kinase inhibitors (TKIs), targeting both receptor and nonreceptor tyrosine kinases. The goal of targeted therapy is to improve antitumor activity with fewer toxic side effects than traditional anticancer therapies; given the initial success of this approach, the number of targeted therapy drugs entering into development in the last 5 years has increased dramatically.6,7 However, several recent studies have revealed unanticipated side effects of targeted therapy, including left ventricular (LV) dysfunction and heart failure, the primary manifestations of cardiotoxicity we will be examining here.5,8,9
Herein, we will examine the potential risk of LV dysfunction of targeted therapy and the molecular mechanisms that underlie that risk. We will review the importance of tyrosine kinase signaling pathways both for oncogenesis and for the survival of normal cardiomyocytes. To understand basic mechanisms of cardiomyopathy of TKIs, it is critical to understand 2 general classes of toxicity. The first
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