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Molecularly Targeted Oncology Therapeutics and Prolongation of the QT Interval

Elizabeth L. Strevel, Douglas J. Ing, Lillian L. Siu

From the Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network; Division of Cardiology, Toronto General Hospital, University Health Network; and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Address reprint requests to Lillian L. Siu, MD, FRCPC, Princess Margaret Hospital, Division of Medical Oncology and Hematology, 610 University Ave, Suite 5-718, Toronto, ON, Canada M5G 2M9; e-mail: lillian.siu{at}uhn.on.ca

Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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