enalapril and Neoplasms

Cardiotoxicity is a common complication that may compromise the clinical effectiveness of anticancer therapy. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, not allowing for any early preventive strategy. Areas covered: A novel approach, based on the use of biomarkers has recently emerged, resulting in a very effective tool for early, real-time identification, and monitoring of cardiotoxicity. In particular, cardiac troponin elevation during chemotherapy allows to identify patients more prone to develop myocardial dysfunction and cardiac events. In these patients, use of angiotensin-converting enzyme inhibitors, such as enalapril, has shown to be effective in improving clinical outcomes, giving the chance for cardioprotective strategies in a selected population. The authors reviewed the currently available data about the role of biomarkers in this setting. Expert commentary: Early identification of patients at high risk of cardiotoxicity by cardiac biomarkers - in particular troponin - provides a rationale for targeted preventive strategies against cancer therapy-induced left ventricular dysfunction and its associated clinical complications, with the advantage of limiting prophylactic therapy only to a restricted number of patients. Although the major international oncologic societies encourage this approach, some limitations to a routinely use of biomarkers still exist.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Biomarkers; Enalapril; Heart Diseases; Humans; Myocardium; Neoplasms; Troponin C

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review.. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015).. Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment.. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.. In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups.. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Topics: Adult; Adult Survivors of Child Adverse Events; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Child; Enalapril; Heart Failure; Humans; Neoplasms; Phosphocreatine; Randomized Controlled Trials as Topic

The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with ≥1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Captopril; Enalapril; Fosinopril; Humans; Lisinopril; Neoplasms; Quinapril; Ramipril; Randomized Controlled Trials as Topic; Tetrahydroisoquinolines

Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit.. The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold.. Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m. Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Agents; Cardiotoxicity; Enalapril; Female; Humans; Male; Middle Aged; Neoplasms; Troponin C; Ventricular Dysfunction, Left

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double-blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril-folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77-1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69-1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07-3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24-0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.

Topics: Adult; Aged; Antihypertensive Agents; China; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Enalapril; Female; Folic Acid; Humans; Hypertension; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Neoplasms; Treatment Outcome

The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy.. The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking.. We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF)

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Agents; Carbazoles; Carvedilol; Cohort Studies; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Neoplasms; Propanolamines; Recovery of Function; Stroke Volume; Treatment Outcome

To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.. This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure.. There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013).. Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

Topics: Adolescent; Adult; Anthracyclines; Child; Child, Preschool; Disease Progression; Double-Blind Method; Enalapril; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Heart Function Tests; Humans; Linear Models; Male; Neoplasms; Probability; Prognosis; Reference Values; Risk Assessment; Severity of Illness Index; Survivors; Treatment Outcome

The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity.. The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure.. A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups.. The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.

Topics: Adolescent; Adult; Age Factors; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Child; Child, Preschool; Disease Progression; Double-Blind Method; Enalapril; Female; Heart Diseases; Heart Function Tests; Humans; Infant; Male; Neoplasms; Placebos; Research Design; Statistics, Nonparametric

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Binding Sites; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colchicine; Drug Design; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Neoplasms; Neovascularization, Physiologic; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Bacteria of micrometer size could accumulate in tumor based on enhanced permeability and retention (EPR) effect. We report here Lactobacillus casei (L. casei), a nonpathogenic facultatively anaerobic bacterium, preferentially accumulated in tumor tissues after intravenously (i.v.) injection; at 24 h, live bacteria were found more in the tumor, whereas the bacteria in normal tissues including the liver and spleen were cleared rapidly. The tumor-selective accumulation and growth of L. casei is probably due to the EPR effect and the hypoxic tumor environment. Moreover, the bacterial tumor delivery was significantly increased by a nitric oxide (NO) donor nitroglycerin (NG, 10-70 times) and an angiotensin II converting enzyme inhibitor, enalapril (6-18 times). Consequently significant suppression of tumor growth was found in a colon cancer C26 model, and more remarkable antitumor effect was achieved when L. casei was combined with NG, probably by modulating the host nonspecific immune responses; tumor necrosis factor-α significantly increased in tumor after the treatment, as well as NO synthase activity and myleoperoxidase activity. These findings suggest the potential of L. casei as a candidate for targeted bacterial antitumor therapy, especially in combine with NG or other vascular mediators.

Topics: Animals; Electron Spin Resonance Spectroscopy; Enalapril; Female; Lacticaseibacillus casei; Male; Mice; Mice, Inbred BALB C; Neoplasms; Nitric Oxide Synthase; Nitroglycerin; Tumor Necrosis Factor-alpha

ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C(20)H(28)N(2)O(5) x C(4)H(4)O(4)) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.

Topics: Acrylates; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Calcium Channel Blockers; Dose-Response Relationship, Drug; Enalapril; Humans; Imidazoles; Indazoles; Lisinopril; Male; Mice; Mice, SCID; Neoplasms; Nifedipine; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Ramipril; Rats; Rats, Sprague-Dawley; Telmisartan; Thiophenes; Xenograft Model Antitumor Assays

Although blocking or pairing before randomization is a basic principle of experimental design, the principle is almost invariably applied to at most one or two blocking variables. Here, we discuss the use of optimal multivariate matching prior to randomization to improve covariate balance for many variables at the same time, presenting an algorithm and a case-study of its performance. The method is useful when all subjects, or large groups of subjects, are randomized at the same time. Optimal matching divides a single group of 2n subjects into n pairs to minimize covariate differences within pairs-the so-called nonbipartite matching problem-then one subject in each pair is picked at random for treatment, the other being assigned to control. Using the baseline covariate data for 132 patients from an actual, unmatched, randomized experiment, we construct 66 pairs matching for 14 covariates. We then create 10000 unmatched and 10000 matched randomized experiments by repeatedly randomizing the 132 patients, and compare the covariate balance with and without matching. By every measure, every one of the 14 covariates was substantially better balanced when randomization was performed within matched pairs. Even after covariance adjustment for chance imbalances in the 14 covariates, matched randomizations provided more accurate estimates than unmatched randomizations, the increase in accuracy being equivalent to, on average, a 7% increase in sample size. In randomization tests of no treatment effect, matched randomizations using the signed rank test had substantially higher power than unmatched randomizations using the rank sum test, even when only 2 of 14 covariates were relevant to a simulated response. Unmatched randomizations experienced rare disasters which were consistently avoided by matched randomizations.

Topics: Adult; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antineoplastic Agents; Cardiac Output; Child; Enalapril; Humans; Matched-Pair Analysis; Neoplasms; Randomized Controlled Trials as Topic; Research Design

A common late effect of doxorubicin therapy for childhood cancer is reduced left-ventricular (LV) wall thickness resulting in elevated LV afterload and depressed LV function. Many children are given angiotensin-converting enzyme inhibitors, which have been studied primarily in adults. We document the long-term effects of angiotensin-converting enzyme inhibitors in doxorubicin-treated survivors of childhood cancer.. In this retrospective study, we reviewed records of 18 children who had regular echocardiographic examinations during enalapril therapy (mean age at cancer diagnosis, 8 years; mean time between completion of doxorubicin therapy and start of enalapril, 7 years; median follow-up since the start of enalapril, 10 years).. Over the first 6 years of enalapril therapy, there was progressive improvement toward normal values in LV dimension, afterload, fractional shortening, and mass, but all these parameters deteriorated between 6 and 10 years. LV wall thickness deteriorated throughout the study period, as did LV contractility and systolic blood pressure. Diastolic blood pressure fell slightly. By 6 years on enalapril, all six patients who had had congestive heart failure at the start of enalapril therapy had either died or undergone cardiac transplantation, compared with three of the 12 asymptomatic patients.. In doxorubicin-treated long-term survivors of childhood cancer, enalapril-induced improvement in LV structure and function is transient. The primary defect, which is LV wall thinning, continues to deteriorate, and thus the short-term improvement was mostly related to lowered diastolic blood pressure.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antihypertensive Agents; Blood Pressure; Child; Death, Sudden, Cardiac; Diastole; Doxorubicin; Drug Administration Schedule; Echocardiography; Enalapril; Heart Failure; Heart Transplantation; Humans; Neoplasms; Retrospective Studies; Risk; Survivors; Ventricular Dysfunction, Left

We describe a new principle for the determination of enzymes, here applied to angiotensin-converting enzyme (ACE, EC 3.4.15.1) in human serum. The enzyme inhibitor binding assay is based on specific binding of labeled inhibitor to the active center of the enzyme. Serum (10-15 microL) is incubated with 125I-labeled ACE inhibitor (" 351A ," a p- hydroxybenzamidine derivative of N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) at pH 7.0 at 37 degrees C for 2 h in a non-equilibrated system. Inhibitor bound to ACE is separated by adsorption to coated charcoal, the radioactivity remaining in the supernate is counted, and the ACE value is calculated from a standard curve. Sensitivity for ACE in serum is 200 U/L, corresponding to 5.0 ng of ACE purified from human lung. The coefficient of variation was 3.9% within assay, and 6.4% between assays for normal ACE activities. Correlation with a comparison spectrophotometric method (Am J Med 59: 363-372, 1975) for ACE assay was excellent (r = 0.98) in 59 samples from healthy subjects and from patients with various diseases including active sarcoidosis. The novel assay principle presented here is simple and specific, and can be extended to use with various biological fluids and tissues, and to other enzymes as well.

Topics: Angiotensin-Converting Enzyme Inhibitors; Binding, Competitive; Chlorides; Dipeptides; Enalapril; Humans; Hydrogen-Ion Concentration; Methods; Neoplasms; Peptidyl-Dipeptidase A; Sarcoidosis; Sulfates