Perspectives in Pharmacology Pharmacological Foundations of Cardio-Oncology

Anthracyclines and many other antitumor drugs induce cardiotoxicity that occurs “on treatment” or long after completing chemotherapy. Dose reductions limit the incidence of early cardiac events but not that of delayed sequelae, possibly indicating that any dose level of antitumor drugs would prime the heart to damage from sequential stressors. Drugs targeted at tumor-specific moieties raised hope for improving the cardiovascular safety of antitumor therapies; unfortunately, however, many such drugs proved unable to spare the heart, aggravated cardiotoxicity induced by anthracyclines, or were safe in selected patients of clinical trials but not in the general population. Cardio-oncology is the discipline aimed at monitoring the cardiovascular safety of antitumor therapies. Although popularly perceived as a clinical discipline that brings oncologists and cardiologists working together, cardio-oncology is in fact a pharmacology-oriented translational discipline. The cardiovascular performance of survivors of cancer will only improve if clinicians joined pharmacologists in the search for new predictive models of cardiotoxicity or mechanistic approaches to explain how a given drug might switch from causing systolic failure to inducing ischemia. The lifetime risk of cardiotoxicity from antitumor drugs needs to be reconciled with the identification of long-lasting pharmacological signatures that overlap with comorbidities. Research on targeted drugs should be reshaped to appreciate that the terminal ballistics of new “magic bullets” might involve cardiomyocytes as innocent bystanders. Finally, the concepts of prevention and treatment need to be tailored to the notion that late-onset cardiotoxicity builds on early asymptomatic cardiotoxicity. The heart of cardio-oncology rests with such pharmacological foundations. Cardiotoxicity of Antitumor Drugs: Old Aspects and New Issues Antitumor drugs have long been known to induce untoward but manageable cardiovascular effects such as transient blood pressure disorders, ischemia, arrhythmias, systolic dysfunction, and pericardial effusions. Hormonal treatment of hormone-responsive tumors also introduces a risk of cardiovascular events. There are cases where the cardiac sequelae of antitumor therapies may be life-threatening; for example, cumulative doses of antibiotics, such as anthracyclines, mitomycin, or mitoxantrone, induce dilative cardiomyopathy and congestive heart failure (CHF) (Minotti et al., 2004; Menna et al., 2008). Almost all of the approved antineoplastics have been shown to induce some type of cardiotoxicity (see Table 1 for a representative list of cardiotoxic drugs). With that said, the clinical manifestations of cardiotoxicity seem to have changed in the last few years. Reducing the cumulative dose of anthracyclines (topoisomerase II inhibitors and DNA intercalators) was of help in diminishing acute or subacute cardiotoxicity but not chronic cardiotoxicity that occurred 5 or more years after completing chemotherapy; moreover, some survivors of cancer developed CHF, whereas others developed ischemic disease and myocardial infarction (MI) (Carver et al., 2007; Swerdlow et al., 2007). Nonanthracycline chemotherapeutics (antimetabolites, alkylators, tubulin-active agents, or other topoisomerase II inhibitors such as etoposide) were known to induce systolic dysfunction but also, if not primarily, ischemia that occurred within hours or This work was supported by Associazione Italiana Ricerca sul Cancro [IG 2004–2008] and University Campus Bio-Medico of Rome [Special Project 1057/08 “Cardio-Oncology”]. E.S. and P.M. contributed equally to this work. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.110.165860. ABBREVIATIONS: CHF, congestive heart failure; MI, myocardial infarction; HER-2, epidermal growth factor receptor 2; VEGF, vascular endothelial growth factor; VEGFr, VEGF receptor; TKI(s), small tyrosine kinase inhibitor(s); LV, left ventricular; LVEF, left ventricular ejection fraction; SHR, spontaneously hypertensive rat; ACEI, angiotensin I-converting enzyme inhibitors; ARB, angiotensin II receptor blockers. 0022-3565/10/3341-2–8$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 334, No. 1 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 165860/3592666 JPET 334:2–8, 2010 Printed in U.S.A. 2 at A PE T Jornals on A ril 1, 2017 jpet.asjournals.org D ow nladed from days of treatment (Menna et al., 2008); however, currently available evidence shows that nonanthracycline chemotherapeutics also introduce a lifetime risk of cardiotoxicity (Carver et al., 2007). The importance of age of first treatment has been reappraised. Children-adolescents and the elderly had long been considered to be more vulnerable by anthracyclines; however, recent studies show that late-onset cardiotoxicity could occur independent of age of first treatment (Swerdlow et al., 2007). Cardiotoxicity is induced by antibodies or small molecules targeted at growth factors, or their receptors, or receptorassociated kinases. Receptors thought to be crucial to tumor cells (e.g., the epidermal growth factor receptor 2, HER-2) are also expressed in cardiomyocytes and relay a number of survival signals (Cheng and Force, 2010). Therefore, blocking HER-2 with the antibody trastuzumab precipitates cardiotoxicity from concomitant anthracyclines or causes dysfunction in patients with prior exposure to anthracyclines (Menna et al., 2008). Antibodies or small tyrosine kinase inhibitors (TKIs) targeted at the vascular endothelial growth factor (VEGF) or its receptors (VEGFr) may cause hypertension, contractile dysfunction, and ischemia (Schmidinger et al., 2008). Imatinib and other TKIs of BcrAbl and C-kit of leukemic or gastrointestinal sarcoma cells are also suspected to cause cardiotoxicity (Cheng and Force, 2010). What Is Cardio-Oncology? Concerns about cardiotoxicity from antitumor drugs should be weighed against survival or curability benefits; for example, anthracyclines caused lifesaving effects that outweighed the risk of cardiac-related death at 10 or 20 years of follow-up (Gianni et al., 2008). Less is known about the recently developed targeted drugs. Studies with a short follow-up demonstrate that commencing trastuzumab after chemotherapy improved the event-free survival of women with HER-2 breast cancer, antiangiogenic drugs were active in many advanced tumors, imatinib was both lifesaving in chronic myeloid leukemia and active in otherwise untreatable gastrointestinal sarcomas (Suter et al., 2007; Albini et al., 2010; Cheng and Force, 2010). These facts show that patients with cancer should not be denied the benefits from drugs with known or suspected cardiotoxicity; similar concepts apply to the elderly as well (Carver et al., 2008). With that said, cardiotoxicity compromises the quality of life and calls for costly medical assistance. Therefore, oncologists and cardiologists were asked to jointly assess the risk/benefit of antitumor therapies and identify the best possible cardiac surveillance or preventative measures that improved the therapeutic index of antitumor therapies. This is the clinical dimension of cardio-oncology (Cardinale, 1996; Gianni et al., 2008), sometimes referred to as onco-cardiology (Albini et al., 2010). Confining cardio-oncology to the merging of cardiology with oncology would be an unforgivable oversight. Cardiooncology is a much broader discipline that goes from bench to bedside and builds clinical initiatives on pharmacological reasoning. In brief, we highlight some contemporary issues that illustrate the pharmacological foundations of cardio-oncology. Lifetime Risk of Cardiotoxicity: A Matter of Long-Lasting Pharmacological Signatures There is an unmet need for deciphering the lifetime risk of cardiotoxicity; this would be much important for drugs, such as the anthracyclines, that are cleared from the heart quite rapidly and decrease to below levels of toxic concern (Salvatorelli et al., 2009). In rats, acute treatment with the anthracycline doxorubicin impaired cardiac oxidative phosphorylation; this was followed by formation of reactive oxygen species that caused both quantitative and qualitative alterations of mitochondrial DNA and its encoded respiratory chain subunits. Inasmuch as mitochondrial dysfunction persisted and worsened after completing anthracycline treatment, these studies suggested that the lifetime risk of cardiotoxicity could be caused by a mitochondriopathy that was self-maintained in the absence of continued exposure to doxorubicin (Lebrecht and Walker, 2007). In humans, however, mitochondriopathy did not correlate with cardiotoxicity induced by other anthracyclines. Post-mortem studies of hearts from patients with cancer showed that mitochondriopathy was caused by doxorubicin but not by its analog epirubicin (Lebrecht and Walker, 2007); in spite of that, epirubicin retained 60% of the cardiotoxic potential of doxorubicin (Menna et al., 2008). The lifetime risk of cardiotoxicity from anthracyclines could be better explained by their conversion to secondary alcohol metabolites. Being more polar than their parent drugs, such metabolites are poorly cleared from cardiomyocytes and accumulate to become a long-lasting anthracycline signature in the heart (Minotti et al., 2004; Menna et al., 2008); moreover, secondary alcohol metabolites are many TABLE 1 Antitumor drugs with known, probable, or presumed cardiotoxicity Anthracyclines and Nonanthracycline Antibiotics Nonanthracycline Chemotherapeutics Targeted Drugs