Cardiotoxicity of Molecularly Targeted Agents

Abstract

Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics.

Vascular Complications of Cancer Chemotherapy

“…Although VEGFIs have been associated with thrombotic and hemorrhagic side effects, 44 , 45 the prothrombotic effects appear to predominate. VEGFIs are associated with an absolute increase in risk of arterial and venous thrombosis and thromboembolism of 1.5%-4%.…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…According to the latest reports, approximately 76 targeted anticancer drugs received approval from the US FDA from 2001 to May 2017; these drugs include small molecule kinase inhibitors, other types of agents (e.g., proteasome and histone deacetylases targeting inhibitors) (Table ), and therapeutic monoclonal antibodies (Tables and ). The clinical patterns of toxicity associated with some of these agents have been addressed or discussed in detail in other reviews . Many of the approved drugs are protein kinase inhibitors (PKIs), typically protein tyrosine kinase inhibitors (TKIs) .…”

“…In addition, targeting the ubiquitin‐proteasome pathway is an emerging concept in cancer therapy based on the hypothesis that many proteins in the proteasome are implicated in the regulation of important processes of carcinogenesis and cancer cell survival . Several proteasome‐targeting inhibitors (e.g., bortezomib, carfilzomib) have been introduced in the clinic. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma reported that bortezomib‐based treatment was associated with a low incidence of cardiac events .…”

“…Two important types of epigenetic changes are DNA methylation by DNA methyltransferases (DNMTs) and histone modification by histone deacetylases (HDACs) . DNMTs and HDACs have become attractive therapeutic targets, and several HDAC inhibitors e.g., Romidepsin, Belinostat, and Panobinostat, have been used in the clinic. Unfortunately, clinical cardiotoxicity has been induced by these types of drugs …”

“…Cardiotoxicity manifests as electrophysiological disorder of the heart (cardiac dysfunction) and a spectrum of myocardial damage (cardiomyopathy), with heart failure as the most severe consequence. The clinical features are demonstrated by a wide range of cardiovascular manifestations or events, including bradycardia, tachycardia, cardiomyopathy, widened pulse pressure, hypotension, arrhythmias, decreased left ventricular ejection fraction (LVEF), troponinemia, QT prolongation, myocarditis, myocardial infarction, pericarditis, acute coronary syndromes, and congestive heart failure . The clinical scenarios derived from these novel anticancer approaches reflect new challenges to medical, pharmacological, and research communities because the cardiotoxicity from new clinical entities are clinically and mechanistically different from the cardiotoxicity resulting from traditional chemotherapeutic agents.…”