Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

Assessment of anthracycline-induced cardiotoxicity in childhood cancer survivors during long-term follow-up using strain analysis and intraventricular pressure gradient measurements.

BACKGROUND: Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in childhood cancer survivors (CCS), and the cumulative incidence of cardiac events has continued to increase. This study identifies an adequate indicator of cardiac dysfunction during long-term follow-up. PROCEDURE: In total, 116 patients (median age: 15.5 [range: 4.7-40.2] years) with childhood cancer who were treated with anthracycline were divided into three age groups for analysis (C1: 4-12 years of age, C2: 13-18 years of age, C3: 19-40 years of age), and 116 control patients of similar ages were divided into three corresponding groups (N1, N2, and N3). Layer-specific strains were assessed for longitudinal strain (LS) and circumferential strain (CS). The total and segmental intraventricular pressure gradients (IVPG) were also calculated based on Doppler imaging of the mitral inflow using Euler's equation. RESULTS: Conventional echocardiographic parameters were not significantly different between the patients and controls. All layers of the LS and inner and middle layers of the basal and papillary CS in all ages and all IVPGs in C2 and C3 decreased compared to those of corresponding age groups. Interestingly, basal CS and basal IVPG in CCS showed moderate correlation and both tended to rapidly decrease with aging. Furthermore, basal IVPG and anthracycline dose showed significant correlations. CONCLUSIONS: Basal CS and total and basal IVPGs may be particularly useful indicators of cardiotoxicity in long-term follow-up.

Assessment of early anthracycline-induced cardiotoxicity and liver injury with T2 and T2* mapping in rabbit models.

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.

Molecular assessment of drug-phospholipid interactions consequent to cancer treatment: a study of anthracycline-induced cardiotoxicity.

Cardiotoxicity limits the use of anthracyclines as potent chemotherapeutics. We employ classical molecular dynamics to explore anthracycline interactions with a realistic myocardial membrane and compare to an ideal membrane widely used in literature. The interaction of these two membranes with four anthracyclines; doxorubicin, epirubicin, daunorubicin, and idarubicin are studied. Careful analysis was conducted on three forms of each drug; pristine, primary metabolite, and cationic salt. By examining the molecular residence time near the membrane's surface, the average number of molecule/membrane hydrogen bonds, the immobilization of the molecules near the membrane, and the location of those molecules relative to the mid-plane of the membrane we found out that salt forms exhibit the highest cardiotoxic probability, followed by the metabolites and pristine forms. Additionally, all forms have more affinity to the upper layer of the realistic myocardial membrane. Meanwhile, an ideal membrane consisting of a single type of phospholipids is not capable of capturing the specific interactions of each drug form. These findings confirm that cardiotoxic mechanisms are membrane-layer and drug-form dependent.

Longitudinal strain analysis for assessment of early cardiotoxicity during anthracycline treatment in childhood sarcoma: A single center experience.

BACKGROUND: The growing population of long-term childhood cancer survivors encounter a substantial burden of cardiovascular complications. The highest risk of cardiovascular complications is associated with exposure to anthracyclines and chest radiation. Longitudinal cardiovascular surveillance is recommended for childhood cancer patients; however, the optimal methods and timing are yet to be elucidated. AIMS: We aimed to investigate the feasibility of different echocardiographic methods to evaluate left ventricular systolic function in retrospective datasets, including left ventricular ejection fraction (LVEF), fractional shortening (FS), global longitudinal strain (GLS) and longitudinal strain (LS) as well as the incidence and timing of subclinical left ventricular dysfunction detected by these methods. METHODS AND RESULTS: A retrospective longitudinal study was performed with re-analysis of longitudinal echocardiographic data, acquired during treatment and early follow-up, including 41 pediatric sarcoma patients, aged 2.1-17.8 years at diagnosis, treated at Astrid Lindgren Children's Hospital, Stockholm, Sweden, during the period 2010-2021. All patients had received treatment according to protocols including high cumulative doxorubicin equivalent doses (≥250 mg/m2 ). In 68% of all 366 echocardiograms, LS analysis was feasible. Impaired LS values (<17%) was demonstrated in >40%, with concomitant impairment of either LVEF or FS in 20% and combined impairment of both LVEF and FS in <10%. Importantly, there were no cases of abnormal LVEF and FS without concomitant LS impairment. CONCLUSION: Our findings demonstrate feasibility of LS in a majority of echocardiograms and a high incidence of impaired LS during anthracycline treatment for childhood sarcoma. We propose inclusion of LS in pediatric echocardiographic surveillance protocols.

In Silico and In Vitro Assessment of Carbonyl Reductase 1 Inhibition Using ASP9521-A Potent Aldo-Keto Reductase 1C3 Inhibitor with the Potential to Support Anticancer Therapy Using Anthracycline Antibiotics.

Anthracycline antibiotics (ANT) are among the most widely used anticancer drugs. Unfortunately, their use is limited due to the development of drug resistance and cardiotoxicity. ANT metabolism, performed mainly by two enzymes-aldo-keto reductase 1C3 (AKR1C3) and carbonyl reductase 1 (CBR1)-is one of the proposed mechanisms generated by the described effects. In this study, we evaluated the CBR1 inhibitory properties of ASP9521, a compound already known as potent AKR1C3 inhibitor. First, we assessed the possibility of ASP9521 binding to the CBR1 catalytic site using molecular docking and molecular dynamics. The research revealed a potential binding mode of ASP9521. Moderate inhibitory activity against CBR1 was observed in studies with recombinant enzymes. Finally, we examined whether ASP9521 can improve the cytotoxic activity of daunorubicin against human lung carcinoma cell line A549 and assessed the cardioprotective properties of ASP9521 in a rat cardiomyocytes model (H9c2) against doxorubicin- and daunorubicin-induced toxicity. The addition of ASP9521 ameliorated the cytotoxic activity of daunorubicin and protected rat cardiomyocytes from the cytotoxic effect of both applied drugs. Considering the favorable bioavailability and safety profile of ASP9521, the obtained results encourage further research. Inhibition of both AKR1C3 and CBR1 may be a promising method of overcoming ANT resistance and cardiotoxicity.

Assessment of Global Cardiac Function Using AutoSTRAIN Automatic Strain Quantitative Technology in Patients With Breast Cancer Undergoing Anthracycline-Based Chemotherapy.

In patients with breast cancer undergoing anthracycline-based chemotherapy, we investigated the deformational parameters of the left ventricle, right ventricle and left atrium, as well as the relationship between these parameters. Ninety-five patients with breast cancer who were treated with anthracycline-based chemotherapy were enrolled. The control group included 116 healthy female volunteers. Parameters including left ventricular global longitudinal strain (LV-GLS); right ventricular free wall longitudinal strain (RVFWSL) and global longitudinal strain (RV4CSL); and peak strain of the left atrium during LV systole (LASR), early LV diastole (LASCD) and late LV diastole (LASCT) were analyzed by speckle tacking echocardiography. LV-GLS, LASR, LASCD, RVFWSL and RV4CSL in the chemotherapy group decreased significantly by 15.6%, 13.8%, 19.8%, 21.8% and 13.2% (p < 0.05), respectively, when compared with the control group. LASCT was slightly increased in the chemotherapy group but the increase was not statistically significant (p > 0.05). Formulas for the influencing factors of LV-GLS were LV-GLS = -18.73738541 + 0.13961 × LVIDd + 0.09672 × LASCD + 0.18113 × RVFWSL in the control group and LV-GLS = -8.026302253 + 0.20811 × LASCD + 0.11084 × LASCT + 0.12153 × RVFWSL in the chemotherapy group. Both LV contraction and RV contraction were impaired after the completion of anthracycline-based therapy, and RVFWSL may be superior to LV-GLS in assessing cardiotoxicity. LA reserve and channel function were significantly reduced, while pump function was slightly increased. Compared with the results among healthy people, the influencing factor of LV-GLS varied after anthracycline treatment, and LA function had a greater impact on LV-GLS.

Cost-Effectiveness of Pharmacologic Treatment Options for Women With Endocrine-Refractory or Triple-Negative Metastatic Breast Cancer.

PURPOSE: Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC. METHODS: Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin. RESULTS: In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options. CONCLUSION: In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling - A case study of doxorubicin with dose metrics considerations.

Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study.

BACKGROUND: Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity. OBJECTIVE: To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy. METHODS: A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up. RESULTS: 94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m2, between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity. CONCLUSIONS: Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study / Evaluación de la cardiotoxicidad temprana asociada al tratamiento con antraciclinas en niños con Leucemia. Estudio prospectivo

Abstract Background: Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity. Objective: To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy. Methods: A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up. Results: 94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m2, between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity. Conclusions: Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Resumen Antecedentes: Las leucemias son la principal causa de cáncer infantil. Los avances en el tratamiento han llevado a los pacientes a una supervivencia global hasta del 80%. Cerca del 10% de los niños con cáncer tienen toxicidad cardiovascular sintomática, la dosis acumulada de antraciclinas es un factor de riesgo para afección cardíaca. Objetivo: Describir la frecuencia de afectación cardíaca temprana en niños con leucemias agudas que recibieron tratamiento antineoplásico. Métodos: Estudio prospectivo observacional, de pacientes <18 años con diagnóstico confirmado de leucemia aguda. Fueron evaluados con electrocardiograma, ecocardiograma bidimensional y biomarcadores séricos en diferentes momentos durante el tratamiento. Resultados: Se evaluaron 94 pacientes con leucemia linfoide aguda y 18 con leucemia mieloide aguda. 20 pacientes (17.9%) tuvieron disfunción cardiaca de inicio temprano. Se observaron diferencias estadísticamente significativas, después de recibir 150 mg/m2 de antraciclinas, entre la evaluación del ecocardiograma basal y evaluaciones posteriores de la fracción de eyección ventricular izquierda por Teicholz p 0.05, fracción de eyección ventricular izquierda por Simpson p 0.018 y la deformación longitudinal global p 0.004. No se encontraron alteraciones en los niveles séricos de las troponinas y péptido natriurético cerebral. Conclusiones: La disfunción cardíaca relacionada con quimioterapia estuvo directamente relacionada con las dosis acumuladas de antraciclinas. En este estudio el uso del ecocardiograma como método de seguimiento permitió identificar factores predictores de riesgo para disfunción cardiaca temprana.

The role of electrochemotherapy with intratumoral bleomycin for early tongue carcinoma.

BACKGROUND: The role of electrochemotherapy (ECT) using intratumoral bleomycin and electroporation as a first line treatment for oral tongue carcinoma has not been defined. AIMS/OBJECTIVES: To evaluate the method of ECT in oral tongue carcinoma. MATERIAL AND METHODS: Twenty-one successive patients with primary T1-T2 oral cancer predominantly of the oral tongue underwent either ECT (test; n = 9), or standard surgical resection and reconstruction (control; n = 12). Outcome variables were: local recurrence rates, 10-year-survival, adverse events, treatment cost, and quality of life. RESULTS: The 10-year local recurrence rate (44.4%) was higher and the tumour-specific survival rate (55.6%) was lower in the ECT group compared to the control group (17% and 91.6%, respectively). Postoperative haemorrhage, dysphagia, and pain were more frequent in ECT patients, treatment time was shorter, but treatment cost was higher. Quality of life was not improved by ECT. CONCLUSIONS AND SIGNIFICANCE: Our results indicate that ECT seems not as suitable for the treatment of early tongue cancer as it is for neoplastic and metastatic skin lesions and less favourable than standard surgical therapy.

Large-Volume Hyperthermia for Safe and Cost-Effective Targeted Drug Delivery Using a Clinical Ultrasound-Guided Focused Ultrasound Device.

Lyso-thermosensitive liposomes (LTSLs) are specifically designed to release chemotherapy agents under conditions of mild hyperthermia. Preclinical studies have indicated that magnetic resonance (MR)-guided focused ultrasound (FUS) systems can generate well-controlled volumetric hyperthermia using real-time thermometry. However, high-throughput clinical translation of these approaches for drug delivery is challenging, not least because of the significant cost overhead of MR guidance and the much larger volumes that need to be heated clinically. Using an ultrasound-guided extracorporeal clinical FUS device (Chongqing HAIFU, JC200) with thermistors in a non-perfused ex vivo bovine liver tissue model with ribs, we present an optimised strategy for rapidly inducing (5-15 min) and sustaining (>30 min) mild hyperthermia (ΔT <+4°C) in large tissue volumes (≤92 cm3). We describe successful clinical translation in a first-in-human clinical trial of targeted drug delivery of LTSLs (TARDOX: a phase I study to investigate drug release from thermosensitive liposomes in liver tumours), in which targeted tumour hyperthermia resulted in localised chemo-ablation. The heating strategy is potentially applicable to other indications and ultrasound-guided FUS devices.

Multiscale and Translational Quantitative Systems Toxicology, Pharmacokinetic-Toxicodynamic Modeling Analysis for Assessment of Doxorubicin-Induced Cardiotoxicity.

Dose-dependent life-threatening doxorubicin-induced cardiotoxicity (DIC) is a major clinical challenge that needs to be addressed. Here, we developed an integrated multiscale and translational quantitative systems toxicology and pharmacokinetic-toxicodynamic (QST-PK/TD) model for optimization of doxorubicin dosing regimens for early monitoring and minimization of DIC. A QST model was established by exposing human cardiomyocytes, AC16 cells, to doxorubicin over a time course, and measuring the dynamics of intracellular signaling proteins, AC16 cell viability and released biomarkers of cardiomyocyte injury such as the B-type natriuretic peptide (BNP). Experiments were scaled up to a three-dimensional and dynamic (3DD) cell culture system to evaluate DIC under various dosing regimens. The PK determinants of doxorubicin influencing DIC were identified in vitro and then translated to the in vivo setting through hybrid physiologically based PK (PBPK)/TD models using preclinical- and clinical-level data extracted from literature. The developed cellular-level QST model captured well the observed dynamics of intracellular proteins, AC16 cell viability and BNP kinetics. In the 3DD setting, dose fractionation of doxorubicin displayed a significant reduction in cardiotoxicity compared to single intravenous doses with equal exposure, implying doxorubicin peak concentrations as the PK determinant for DIC. The in vivo hybrid PBPK/TD models captured well doxorubicin PK and DIC. Peak doxorubicin concentrations correlated well with acute DIC for dose-fractionated regimens, while maximum 48-h moving average concentrations correlated with DIC for dose-fractionated and long-term infusion regimens in vivo. The developed multiscale and translational QST-PK/TD modeling platform may serve as an in silico tool for assessment of early toxicity and/or efficacy of developmental drugs in vitro.

Assessment of the Nutraceutical Effects of Oleuropein and the Cytotoxic Effects of Adriamycin, When Administered Alone and in Combination, in MG-63 Human Osteosarcoma Cells.

Oleuropein (OLEU) is the most distinguished phenolic compound found in olive fruit and the leaves of Olea europaea L., with several pharmacological properties, including anti-cancer actions. Adriamycin (ADR) is an anthracycline widely used as a chemotherapeutic agent, although it presents significant side effects. The aim of the present study was to investigate the effect of oleuropein alone (20 µg/mL) and in co-treatment with ADR (50 nM), in MG-63 human osteosarcoma cells. Therefore, cellular and molecular techniques, such as MTT assay, flow cytometry, real-time Polymerase Chain Reaction (PCR), western blot and Elisa method, as well as Nuclear Magnetic Resonance (NMR) spectroscopy, were applied to unveil changes in the signal transduction pathways involved in osteosarcoma cells survival. The observed alterations in gene, protein and metabolite levels denote that OLEU not only inhibits MG-63 cells proliferation and potentiates ADR's cytotoxicity, but also exerts its action, at least in part, through the induction of autophagy.

An assessment of the protective effect of gonadotropin-releasing hormone agonist and antagonist on bleomycin-induced ovarian toxicity in rats.

The aim of this study is to evaluate the effect of GnRH agonist or GnRH antagonist therapy on bleomycin-administered rats by examining ovarian follicle counts and AMH levels. A total of 30 female Wistar albino rats aged 4-6 months were randomly divided into 4 groups. First, an intramuscular injection of bleomycin (30 mg/m2) was administered to all except the control group on the 1st, 8th and 15th days. The control group (Group I) was administered 0.1 mL intramuscular saline on those days. The bleomycin group (Group II) was followed up without any further treatment. The bleomycin + GnRH agonist group (Group III) was administered subcutaneous GnRH agonist triptorelin (1 mg/kg) at the same time as the bleomycin injections. The bleomycin + GnRH antagonist group (Group IV) was administered 1 mg/kg cetrorelix acetate subcutaneously, concurrently with the bleomycin. Although AMH levels were lower in the bleomycin group than in all the other groups, there was no statistically significant difference between the groups in terms of AMH levels (p > .05). In the bleomycin + cetrorelix acetate and bleomycin + triptorelin groups, significantly higher primordial, secondary and tertiary follicle counts were determined compared to the bleomycin group (p < .001). In conclusion the harmful effects of bleomycin on ovarian reserve can be reduced by the simultaneous administration of GnRH agonist or GnRH antagonist.

Comparison of Drug-Eluting Embolics versus Conventional Transarterial Chemoembolization for the Treatment of Patients with Unresectable Hepatocellular Carcinoma: A Cost-Effectiveness Analysis.

PURPOSE: To compare the cost-effectiveness of using doxorubicin-loaded drug-eluting embolic (DEE) transarterial chemoembolization versus that of using conventional transarterial chemoembolization for patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A decision-analysis model was constructed over the lifespan of a payer's perspective. The model simulated the clinical course, including periprocedural complications, additional transarterial chemoembolization or other treatments (ablation, radioembolization, or systemic treatment), palliative care, and death, of patients with unresectable HCC. All clinical parameters were derived from the literature. Base case calculations, probabilistic sensitivity analyses, and multiple two-way sensitivity analyses were performed. RESULTS: In the base case calculations for patients with a median age of 67 years (range for conventional transarterial chemoembolization: 28-88 years, range for DEE-transarterial chemoembolization: 16-93 years), conventional transarterial chemoembolization yielded a health benefit of 2.11 quality-adjusted life years (QALY) at a cost of $125,324, whereas DEE-transarterial chemoembolization yielded 1.71 QALY for $144,816. In 10,000 Monte Carlo simulations, conventional transarterial chemoembolization continued to be a more cost-effective strategy. conventional transarterial chemoembolization was cost-effective when the complication risks for both the procedures were simultaneously varied from 0% to 30%. DEE-transarterial chemoembolization became cost-effective if the conventional transarterial chemoembolization mortality exceeded that of DEE-transarterial chemoembolization by 17% in absolute values. The two-way sensitivity analyses demonstrated that conventional transarterial chemoembolization was cost-effective until the risk of disease progression was >0.4% of that for DEE-transarterial chemoembolization in absolute values. Our analysis showed that DEE-transarterial chemoembolization would be more cost-effective if it offered >2.5% higher overall survival benefit than conventional transarterial chemoembolization in absolute values. CONCLUSIONS: Compared with DEE-transarterial chemoembolization, conventional transarterial chemoembolization yielded a higher number of QALY at a lower cost, making it the more cost-effective of the 2 modalities.

Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment.

Although doxorubicin (Dox) is an effective antitumor antibiotic in the anthracycline class, it often induces the undesirable side effect of cardiomyopathy leading to congestive heart failure, which limits its clinical use. The primary goal of this study is to evaluate a reliable translational method for Dox-induced cardiotoxicity (CTX) screening, aiming to identify a high-risk population and to discover new strategies to predict and investigate this phenomenon. Early identification of the presence of iron deposits and genetic and environmental triggers that predispose individuals to increased risk of Dox-induced CTX (e.g., overexpression of Toll-like receptor 4 (TLR4)) will enable the early implementation of countermeasure therapy, which will improve the patient's chance of survival. Our cohort consisted of 25 consecutive patients with pathologically confirmed cancer undergoing Dox chemotherapy and 12 control patients. The following parameters were measured: serum TLR4 (baseline), serum transferrin (baseline and 6-week follow-up) and iron deposition (baseline and 6-week follow-up). The average number of gene expression units was 0.121 for TLR4 (range 0.051-0.801). We subsequently correlated serum TLR4 levels in our cohort with myocardial iron overload using the cardiac magnetic resonance (CMR) T2* technique, the ventricular function (% ejection fraction, %EF) and serum transferrin levels. There is a strong negative linear relationship between serum TLR4 and CMR T2* values (r = - 0.9106, ****P < 0.0001). There is also a linear correlation (either positive or negative) with EF and transferrin; no established relationship related to the sex of the patients was found. Patients with elevated serum TLR4 at baseline also exhibited an increase in serum transferrin levels and Dox-induced left ventricular dysfunction with a decreased EF (< 50%); this phenomenon was observed in 7 of 25 patients (28%) at the 6-week follow-up. There were no significant differences or correlations based on sex. We concluded that there is a direct relationship between Dox-induced CTX (indicated by elevated serum TLR4) and the times (ms) for T2* (decreases in which correspond to immediate and rapid iron overload).

In vitro vascular toxicity assessment of NitDOX, a novel NO-releasing doxorubicin.

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.hy926 cell viability, on the mechanical activity of freshly and cultured rat aorta rings, as well as on Cav1.2 channels of A7r5 cells. DOX was used as a reference compound. Although an increase in intracellular radicals and a reduction in mitochondrial potential occurred upon treatment with both drugs, A7r5 and EA.hy926 cells proved to be more sensitive to DOX than to NitDOX. Both compounds promoted comparable effects in A7r5 cells, whereas NitDOX was less active than DOX in inducing DNA damage and in eliciting apoptotic-mediated cell death revealed as an increase in sub-diploid-, DAPI- and annexin V-positive- EA.hy926 cell percentage. Moreover, in EA.hy926 cells, NitDOX doubled basal NO content, while preincubation with the NO-scavenger PTIO increased NitDOX-induced cytotoxicity. DOX exhibited a negligible contracturing effect in endothelium-intact rings, while NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. In arteries cultured with both drugs for 7 days, NitDOX prevented either phenylephrine- or KCl-induced contraction at a concentration 10-fold higher than that of DOX. These results demonstrate that NitDOX displays a more favourable vascular toxicity profile than DOX. Taking into account its greater efficacy against drug-resistant cells, NitDOX is worth of further investigations in preclinical and clinical settings.