Doxorubicin-related Cardiotoxicity Research Articles

Depletion of SASP senescent cardiomyocytes with senolytic drugs confers therapeutic effects in doxorubicin-related cardiotoxicity.

Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing thesesenescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H2A.X was used to assess the SASP in the Dox-treated heart. To explore the molecular mechanisms involved, the Bcl-2 inhibitor ABT-199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl-2, although treatment of mice with ABT-199 selectively eliminated SASP senescent cardiomyocytes involved in Dox-induced cardiotoxicity, thus leading to partial alleviation of Dox-induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox-dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox-induced cardiac injury.

Cardiac Mechanical Performance Assessment at Different Levels of Exercise in Childhood Acute Lymphoblastic Leukemia Survivors.

There is a shortage of relevant studies interested in cardiac mechanical performance. Thus, it is clinically relevant to study the impact of cancer treatments on survivors' cardiac mechanical performance to improve our knowledge. The first objective of this study is to assess survivors' cardiac mechanical performance during a cardiopulmonary exercise test (CPET) using both ventricular-arterial coupling (VAC) and cardiac work efficiency (CWE) from cardiac magnetic resonance (CMR) acquisitions. The second objective is to assess the impact of doxorubicin and dexrazoxane (DEX) treatments. A total of 63 childhood acute lymphoblastic leukemia survivors underwent a CMR at rest on a 3T magnetic resonance imaging system, followed by a CPET on ergocycle. The CircAdapt model was used to study cardiac mechanical performance. At different levels of exercise, arterial elastance, end-systolic elastance, VAC, and CWE were estimated. We observed significant differences between the different levels of exercise for both VAC ( P <0.0001) and CWE parameters ( P =0.001). No significant differences were reported between prognostic risk groups at rest and during the CPET. Nevertheless, we observed that survivors in the SR group had a VAC value slightly lower than heart rate (HR)+DEX and HR groups throughout the CPET. Moreover, survivors in the SR group had a CWE parameter slightly higher than HR+DEX and HR groups throughout the CPET. This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.

Modelling cardiac mechanics in doxorubicin-induced cardiotoxicity following childhood acute lymphoblastic leukemia using a combination of cardiac magnetic resonance imaging, cardiopulmonary exercise testing and the CircAdapt model

Children with acute lymphoblastic leukemia (ALL) are treated with doxorubicin-based chemotherapy that can lead to cardiotoxicity which is a well-known cause of mortality. This study aims to characterize myocardial subtle changes induced by doxorubicin-related cardiotoxicity. We used the combination of cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing and the CircAdapt model to explore hemodynamics and intraventricular mechanisms at rest and during exercise in 53 childhood ALL survivors. A sensitivity analysis of the CircAdapt model identified the most influencing parameters on the left ventricle volume. ANOVA were performed to explore significant differences between left ventricle stiffness, contractility, and arteriovenous pressure drop, as well as survivors’ prognostic risk groups. No significant differences were observed between prognostic risk groups. The left ventricle stiffness and left ventricle contractility were non-significantly higher in survivors receiving cardioprotective agents (94.3 %), compared to those at standard and high prognostic risk (77 % and 86 %, respectively). In both left ventricle stiffness and left ventricle contractility, we observed that survivors receiving cardioprotective agents were close to the nominal value of CircAdapt (healthy reference group value is 100 %). This study allowed to improve our knowledge of potential subtle myocardial changes induced by doxorubicin-related cardiotoxicity in childhood ALL survivors. This study confirms that survivors exposed to a high cumulative dose of doxorubicin during treatments are at potential risk of myocardial changes many years after the end of their cancer, while cardio-protective agents may prevent changes in cardiac mechanical properties.

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity.

Doxorubicin is one of the most common antitumor drugs. However, cardiotoxicity's side effect limits its clinical applicability. In the present study, Gene Expression Omnibus (GEO) datasets were applied to reanalyze differentially expressed genes (DEGs) and construct weighted correlation network analysis (WGCNA) modules of doxorubicin-induced cardiotoxicity in wild-type mice. Several other bioinformatics analyses were performed to pick out the hub gene, and then the correlation between the hub gene and immune infiltration was evaluated. In total, 120 DEGs were discovered in a mouse model of doxorubicin-induced cardiotoxicity, and PF-04217903, propranolol, azithromycin, etc. were found to be potential drugs against this pathological condition. Among all the DEGs, 14 were further screened out by WGCNA modules, of which Limd1 was upregulated and finally regarded as the hub gene after being validated in other GEO datasets. Limd1 was upregulated in the peripheral blood mononuclear cell (PBMC) of the rat model, and the area under curve (AUC) of the receiver operating characteristic curve (ROC) in diagnosing cardiotoxicity was 0.847. The GSEA and PPI networks revealed a potential immunocyte regulatory role of Limd1 in cardiotoxicity. The proportion of "dendritic cells activated" in the heart was significantly elevated, while "macrophage M1" and "monocytes" declined after in vivo doxorubicin application. Finally, Limd1 expression was significantly positively correlated with "dendritic cells activation' and negatively correlated with "monocytes" and "macrophages M1'. In summary, our results suggested that limd1 is a valuable biomarker and a potential inflammation regulator in doxorubicin-induced cardiotoxicity.

Baicalin regulates TLR4/IκBα/NFκB signaling pathway to alleviate inflammation in Doxorubicin related cardiotoxicity

Cancers and the toxic and side effects of their treatment have always been a major problem for human beings. Doxorubicin (DOX) is one of the classical anthracycline antineoplastic drugs, but it can cause different degrees of heart damage and even serious heart failure. The incidence of myocardial toxicity increased significantly when the cumulative dose of the drug was more than 550mg/m2, and the relevant mechanism was related to the inflammatory reaction, reactive oxygen species and the apoptosis of cardiomyocytes in the myocardium. Relevant studies have shown that baicalein (Ba) can inhibit NFκB-related inflammatory signaling pathway protects cardiac function, but whether it can inhibit DOX induced cardiotoxicity has not been reported. Therefore, in animal studies, we explored the effects of doxorubicin and baicalein on cardiac function, TLR4/IκBα/NFκB signaling pathway and related inflammatory indicators in rats. In cell experiments, by silencing or overexpressing TLR4, we explored whether baicalein could achieve anti-inflammatory effect through regulating TLR4/IκBα/NFκB signaling pathway and ultimately inhibit doxorubicin induced cardiotoxicity.

MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling.

Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.

Detection of doxorubicin-induced cardiotoxicity using myocardial T1 and T2 relaxation times in childhood acute lymphoblastic leukemia survivors.

Doxorubicin leads to dose-dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. The first aim was to propose a contour-based estimation of T1 and T2 relaxation times based on the myocardial area, while our second aim was to evaluate native T1, post-gadolinium T1 and T2 relaxation time sensitivity to detect myocardial changes. A total of 84 childhood ALL survivors were stratified in regard to their prognostic risk groups: standard risk (SR), n = 20), high-risk with and without dexrazoxane (HR + DEX, n = 39 and HR, n = 25). Survivors' mean age was of 22.0 ± 6.9years, with a mean age at cancer diagnosis of 8.0 ± 5.2years. CMR acquisitions were performed on a 3T MRI system and included an ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Myocardial contours were semi-automatically segmented using an interactive implementation of cubic Bezier curves. We found excellent repeatability between operators for native T1 (ICC = 0.91), and good repeatability between operators for post-gadolinium T1 (ICC = 0.84) and T2 (ICC = 0.79). Bland and Altman tests demonstrated a strong agreement between our contour-based method and images analyzed using the CVI42 software on the measure of native T1, post-gadolinium T1, and T2. No significant differences between survivors' prognostic risk groups in native T1 were reported, while we observed significant differences between survivors' prognostic risk groups in post-gadolinium T1 and T2. Significant differences were observed between male and female survivors. Differences between groups were also observed in partition coefficients, but no significant differences were observed between male and female survivors. The use of CMR parameters with native T1, post-gadolinium T1, and T2 allowed to show that survivors at a high-risk prognostic were more exposed to doxorubicin-related cardiotoxicity than those who were at a standard risk prognostic or who received dexrazoxane treatments.

An Assessment of Race as a Risk Factor for Doxorubicin-Related Cardiotoxicity in Diffuse Large B-Cell Lymphoma

BackgroundDoxorubicin carries a risk of congestive heart failure (CHF). Black race has been suggested as a risk factor for doxorubicin-related cardiotoxicity, but data are limited. We assessed whether HF occurs at higher rates in Black patients compared to White patients who receive doxorubicin for DLBCL, and evaluated race as an independent risk factor for the development of HF after adjusting for known risk factors. Patients and MethodsWe used SEER-Medicare to identify patients 66 years and older with DLBCL. We excluded patients with CHF documented prior to diagnosis with DLBCL. We assessed for hypertension, type 2 diabetes, coronary artery disease, and arrhythmias prior to diagnosis with DLBCL. The primary outcome was documented CHF at any point following DLBCL diagnosis. Secondary outcomes included CHF in the first year following diagnosis and death. We performed analyses additionally stratified by cumulative dose of doxorubicin. ResultsOur study population consisted of 8,604 patients (White 96.8%, Black 3.2%). In both Kaplan-Meier and competing risk analyses, we observed no significant difference in the incidence of CHF between Black and White patients, both before and after adjusting for covariates. Finally, we observed no significant differences in the incidence of CHF by race after stratification by cumulative doxorubicin dose. ConclusionsCHF is common following doxorubicin chemotherapy for DLBCL in older patients. No association was observed between Black race and the onset of heart failure in this setting. Rigorous screening for known clinical risk factors is likely more relevant than race in treatment selection and optimization.

Research progress of exosomes in the treatment of doxorubicin-related cardiotoxicity

阿霉素是一种用于血液和实体肿瘤治疗的一线化疗药物，但是阿霉素在癌症治疗中产生的心肌毒性限制了其应用。目前，没有一种药物能明确降低阿霉素的心肌损害。外泌体是由细胞分泌的生物性囊泡，在细胞之间物质交换和信号传递中起着重要作用。近年来，外泌体在心脏的保护作用被发现。也有研究表明，外泌体可以治疗阿霉素的心肌毒性。本文概述阿霉素心肌毒性的机制，并探究外泌体作为对抗阿霉素心肌毒性的辅助疗法的作用及其机制。.

Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

BackgroundThe incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening.ResultsIn the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes.ConclusionsOur results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

Interleukin-10 Levels are Associated with Doxorubicin-Related Cardiotoxicity in Breast Cancer Patients in a One-Year Follow-Up Study

ABSTRACT Background Myocardial toxicity is a common side effect of doxorubicin (DOXO) therapy in breast cancer patients. We hypothesized that DOXO-induced cardiotoxicity may be related to the release of inflammatory cytokines in response to the treatment. This study aimed to assess changes in plasma levels of interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor (TNF) after chemotherapy and to correlate these levels with cardiac biomarkers and clinical data. Methods Sixty-four patients with breast cancer treated with DOXO were included. Twenty-two subjects (cases) developed cardiotoxicity until one year after the end of DOXO treatment. Cytokines and cardiac markers were evaluated before starting chemotherapy (T0), up to 7 days after the last infusion (T1) and 12 months after the last infusion (T2). Results Higher IL-10 levels were observed in the case group compared to controls at T1 (p = .006) and T2 (p = .046). The IL-1β, IL-6 and TNF levels did not change during treatment in each group (p > .05), nor between the case and control groups. The IL-10 levels were higher at T1 than at T0 and T2 (p < .05 for both) in the cardiotoxicity group. A correlation between IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at T0 and T2 in the cardiotoxicity group was observed (p = .048 and p = .004, respectively). Conclusion Our study demonstrated that DOXO induced an increase in plasma IL-10 levels in patients who presented cardiotoxicity after treatment, which correlated with NT-proBNP levels.

An Assessment of Race As a Risk Factor for Doxorubicin-Related Cardiotoxicity in Diffuse Large B Cell Lymphoma

Introduction Doxorubicin carries a risk of heart failure (HF). Black race has been suggested as a risk factor for doxorubicin-related HF or asymptomatic LVEF decline, but studies were limited by small sample size, unknown racial composition of the comparison group, or lack of assessment of potential confounders. We aimed to assess whether HF occurs at higher rates in black patients (pts) compared to non-Hispanic white pts who receive doxorubicin for DLBCL, and to evaluate race as an independent risk factor for the development of HF after adjusting for known risk factors. Methods We used the Surveillance, Epidemiology, End Results - Medicare (SEER-Medicare) database to identify pts &gt;65 years who were diagnosed with DLBCL (ICD-O: 9680, 9684) between 1997-2015 and who received doxorubicin (HCPCS/NDC codes) within 30 days of diagnosis. We excluded pts with HF (ICD-9: 428, ICD-10: I50) documented prior to diagnosis with DLBCL. We recorded age at diagnosis, Ann Arbor stage, and race. We assessed pts for hypertension (HTN) and coronary artery disease (CAD) documented in the year prior to lymphoma diagnosis. The primary outcome was documented HF at any point following DLBCL diagnosis. Descriptive statistics were performed for demographic and clinical variables. The proportion of pts who developed HF was calculated in both racial groups and compared with the chi-square test. A multivariable logistic regression model was formulated using race, age at diagnosis, Ann Arbor stage and comorbidities, as covariates. Adjusted odds ratios and 95% confidence intervals for racial group status and demographic/clinical variables of interest were estimated from the multivariable model. The Kaplan-Meier method was used to generate time-to-event curves for the onset of HF in each racial group. A multivariable Cox proportional hazards model was used to estimate the hazard ratio for the diagnosis of HF in black vs. white pts after adjusting for age at diagnosis, stage, HTN and CAD. All p-values were two-sided with statistical significance evaluated at the 0.05 alpha level. Results We identified 71,072 pts with DLBCL (white 82.2%, black 5.7%). We excluded 13,651 (19%) pts with HF prior to lymphoma diagnosis (white 84.4%, black 5.7%). We identified 6630 pts (white 88.8%, black 3%) with DLBCL who had received doxorubicin within 30 days of diagnosis. We excluded 797 pts &lt;65 years and 802 pts with unknown stage at diagnosis. Of the remaining 4555 pts (white 97.7%, black 2.3%), 3398 (74.6%) had a history of HTN (white 74.3%, black 88.7%) and 1841 (40.4%) had a history of CAD (white 40.5%, black 37.7%). A total of 1607 (35%) pts developed HF (white 35%, black 33%). By univariate analysis, factors associated with development of HF included history of HTN (OR 1.27; 95% CI 1.10-1.47; p=0.001), CAD (OR 1.39; 95% CI 1.23-1.57); p&lt;0.001), age at diagnosis of DLCBL (median 72.5 vs. 74; p=&lt;0.001) and stage (OR 0.87; 95% CI 0.77-0.98; p=0.02). Race was not associated with risk of HF (OR 1.11; 95% CI 0.74-1.68; p=0.70). Our multivariable logistic regression model showed that older age at diagnosis (OR 1.03; 95% CI 1.02-1.04) and CAD (OR, 1.28; 95% CI 1.12-1.46) were associated with HF. Stage III/IV (OR 0.86; 95% CI 0.76-0.97) was associated with a lower risk of HF compared to stage I/II. Race (OR 1.05; 95% CI 0.70-1.60) and prior history of HTN (OR 1.12; 95% CI 0.96-1.30) were not significantly associated with development of HF. The median overall CHF-free survival time was 10.28 years after diagnosis (95% CI 9.75-11.13; Figure 1). Log-rank testing showed no difference in probability of developing HF between black and white pts (p=0.80), and the Cox model showed that after accounting for age at diagnosis, stage, HTN, and CAD, there was no statistically significant association between race and HF (HR, 0.92; 95% CI 0.66-1.30; p=0.62). Discussion HF is a common condition in older individuals following use of anthracycline for DLBCL, and it is associated with worse survival. No association was observed between black race and the onset of heart failure following treatment with doxorubicin for DLBCL. However, there was a greater proportion of black pts excluded for pre-existing HF than in the final study population. This highlights the importance of rigorous screening for pre-existing HF or LV dysfunction as a means of mitigating the risk of worsening cardiac function in this population. Figure 1 Disclosures Martin: I-MAB: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Janssen: Consultancy.

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children\u2019s Oncology Group

BackgroundDexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.MethodsWe evaluated children with osteosarcoma (OS) on two Children’s Oncology Group trials with higher dose doxorubicin (375–600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.ResultsAll children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P < 0.01) and LV mass Z-scores (P < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass Z-scores were significantly smaller for girls (P < 0.01) and marginally smaller for boys (P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.ConclusionsDexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.Trial registrationsClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin

Doxorubicin (DOX) is an antitumor drug widely used in hematological tumors and various solid tumors. However, the cardiotoxicity elicited by DOX severely limits its clinical treatment. Dimethyl itaconate (DI), a common form of itaconate, is found many potential targets for prevent heart injury. Here we employed wild type and Nrf2 knockout mice and induced a cardiotoxicity model by administration of DOX to clarify the effects of DI. After treatment with DI, we found that it could effectively alleviate the cardiotoxicity by analyzing morphology, LDH levels and heart weight/body weight ratio changes. Meanwhile we demonstrated that RIP3, a key protein of necrosis, was significantly decreased in DI treated group. Further we observed that treatment with DI could suppress oxidative stress by altering Nrf2/HO-1. Compared with vehicle group, DI could increase the tissue SOD and GSH, and reduce MDA levels, then DHE staining revealed that the level of ROS in DI group reduced by half. Finally, transmission electron microscope (TEM) data showed that treatment with DI obviously decreased the mitochondrial damage. While Nrf2 was ablated in mice, the protective effects of DI were vanished and SOD, GSH, MDA became unchanged related to vehicle group. This report provides the evidence for the protective effects of DI treatment in cardiotoxicity induced by DOX. On mechanisms, DI could reduce the oxidative stress by altering Nrf2/HO-1 pathway and prevent mitochondrial from damage. Taken together, these findings of this paper will afford the new therapeutic targets in DOX related cardiotoxicity.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen

Background: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or β-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. Methods: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. Results: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. Conclusions: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

The Correlation between the Level of Doxorubicin-Induced Cardiac Damage and Serum Soluble Fas in an Experimental Rat Model

Abstract Aim: This study was planned to research the relationship between doxorubicin cardiomyopathy and the soluble Fas (sFas) level. Materials and Methods: Two groups of rats were included in the study. The control group was given physiological saline, while the study group was given doxorubicin. The rats, whose blood samples were taken weekly, were sacrificed and their myocardial tissues were removed. The tissues were examined in terms of morphological changes and surface Fas expression, while the blood samples were examined in terms of sFas level. Results: In the study group, the sFas levels at 2nd–9th weeks were higher than those found at 1st week before administrating the drug, and the increase at 2nd–7th weeks was meaningful. In addition, sFas levels were gradually increased each week during 1st–5th weeks when compared to the values of a previous week, and the increase during the first 4 weeks was meaningful. After the 5th week, the values gradually decreased each week. The mean values of the study group at 1st–8th weeks were higher than those of the control group, and the increases at 2nd–8th weeks were meaningful. The severe forms of interfibrillar hemorrhage, vascular dilatation, myocardial necrosis, inflammatory infiltration, and splitting of muscle fibers occurred with 15, 15, 17.5, 20, and 22.5 mg/kg dose of medicine, respectively. Conclusions: As the tissue injury increased, the increasing cell-surface Fas expression and sFas plasma level at the acute phase of doxorubicin-related cardiotoxicity decreased. The sFas level determined at acute phase may be helpful in predicting the existing injuries and possible late-term problems.

Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial

Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. See Acknowledgments for funders.

Cardioprotective Effect of Clarithromycin on Doxorubicin-Induced Cardiac Toxicity in Rats.

Doxorubicin is an anthracycline group antibiotic and has long been used as an antineoplastic agent. The most important side effect that limits the usage of doxorubicin is cardiotoxicity, which is observed at cumulative doses. We investigated the protective effect of clarithromycin that is known to have antioxidant and anti-inflammatory effects against Doxorubicin related cardiotoxicity. The aim of our study was to evaluate the effects of clarithromycin in the antioxidant enzyme status and myocardium of doxorobucine-treated rats. A total of 28 adult, male Wistar rats (200-250 g) were divided into 4 groups. Group I was the control group, rats in group 2 were administered doxorubicin, rats in group 3 were administered clarithromycin, and rats in group 4 were administered Doxorubicin + Clarithromycin. Following the scarification of all rats, antioxidant (glutathione) and oxidant (malodialdehyde) levels were measured in the cardiac tissue. Additionally, the cardiac muscles were evaluated histopathologically via hematoxylin eosin staining. The antioxidant amount (glutathione) was significantly higher in the treatment group compared to the doxorubicin group (p= 0.025), whereas the amount of oxidant (malondialdehyde) was significantly lower (p= 0.022). The histopathological examination revealed significant cardiotoxicity in the Doxorubicin group and significant reduction in the cardiotoxicity in the Doxorubicin + Clarithromycin group. The results obtained in this study provide evidence for the usefulness of the clarithromycin as a cardioprotective agent.

Trastuzumab and Doxorubicin-Related Cardiotoxicity and the Cardioprotective Role of Exercise

Women diagnosed with breast cancer typically undergo a multimodal approach to treating their disease. The treatments used often result in sequelae such as fatigue, hair loss, nausea and vomiting, and functional impairment. Many of these sequelae can be controlled or eliminated with pharmacological, physical, or social interventions. However, 2 effective cytotoxic agents, doxorubicin and trastuzumab, are associated with a potentially life-threatening sequela, cardiotoxicity. Currently, these agents are dosage and duration limited to circumvent cardiac damage. Exercise prior to and during the administration of these agents is emerging as a possible cardioprotective intervention based on the findings of animal model studies. Incorporating exercise into the breast cancer treatment trajectory may eliminate the dosage and duration restrictions of these antineoplastic agents and ultimately affect survival and quality of life. The authors present the pharmacological mechanism for each agent and the exciting results of animal model studies that lay the groundwork for future clinical trials.

Dystrophin‐deficiency increases the susceptibility to doxorubicin‐induced cardiotoxicity

The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity. Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays. DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death. Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins.