RESUMO
OBJECTIVE: The objective of this study was to investigate the impact of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in osteosarcoma patients and analyze the factors influencing this effect. METHODS: A retrospective study was conducted on 165 osteosarcoma patients admitted to our hospital from January 2020 to December 2022. Based on the chemotherapy regimen, the patients were divided into two groups: the control group (n = 62) treated with Cisplatin and cyclophosphamide, and the observation group (n = 103) treated with Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline). The general records of both groups were analyzed, and left ventricular ejection fraction (LVEF) was evaluated through echocardiography before and after chemotherapy. Blood cTnT and CK-MB levels were measured using immunoluminescence. The incidence of adverse reactions during chemotherapy was also analyzed. Univariate analysis was performed to identify patients with cardiotoxic events, and multiple logistic regression analysis was done to study the effects of Doxorubicin, Epirubicin, Liposomal Doxorubicin, and their dosages on cardiotoxicity in patients. RESULTS: The general records between the two groups showed no significant differences (P > 0.05). However, at the fourth cycle of chemotherapy, the observation group exhibited a lower LVEF (P < 0.05), and a higher percentage of LVEF decrease compared to the control group (P < 0.05). Moreover, the observation group had higher levels of blood cTnT and CK-MB (P < 0.05). The incidence of cardiotoxicity in the observation group was also higher (P < 0.05), but no significant differences were seen in other adverse reaction rates (P > 0.05). The occurrence of cardiotoxicity was found to be related to the choice and dosage of chemotherapy drugs (P < 0.05), but not significantly correlated with age, sex, and mediastinal irradiation in patients (P > 0.05). Furthermore, the use of Doxorubicin, Epirubicin, and Liposomal Doxorubicin in chemotherapy, as well as an increase in their dosages, was found to elevate the risk of cardiotoxicity in osteosarcoma patients (P < 0.05). However, age, sex, and mediastinal radiation were not significantly associated with cardiotoxicity in osteosarcoma patients (P > 0.05). CONCLUSION: We demonstrated that Doxorubicin, Epirubicin, Liposomal Doxorubicin (Anthracycline), and other drugs adversely affected cardiac function in osteosarcoma patients, increasing the risk of cardiac toxicity. Therefore, close monitoring of cardiac function during chemotherapy is crucial, and timely adjustments to the chemotherapy regimen are necessary. In addition, rational control of drug selection and dosage is essential to minimize the occurrence of cardiac toxicity.
Assuntos
Neoplasias Ósseas , Cardiotoxicidade , Doxorrubicina , Epirubicina , Osteossarcoma , Humanos , Osteossarcoma/tratamento farmacológico , Epirubicina/efeitos adversos , Epirubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Masculino , Estudos Retrospectivos , Adulto , Adulto Jovem , Neoplasias Ósseas/tratamento farmacológico , Cardiotoxicidade/etiologia , Adolescente , Volume Sistólico/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/uso terapêutico , Ecocardiografia , Troponina T/sangue , Creatina Quinase Forma MB/sangue , Ciclofosfamida/efeitos adversos , Ciclofosfamida/administração & dosagem , Criança , Cisplatino/efeitos adversos , Cisplatino/administração & dosagem , PolietilenoglicóisRESUMO
PURPOSE: Thoracic sarcomas are rare malignancies, with limited data for unresectable/advanced scenarios. Our goal is to provide insights of a three-drug chemotherapy regimen improving patient survival compared to standard regimens. METHODS: Retrospective cohort analysis of patients diagnosed with unresectable/advanced primary thoracic sarcoma divided between primary pulmonary sarcomas (PPS) and chest wall sarcomas (CWS) comparing chemotherapeutical regimens efficacy. Not true soft tissue sarcomas (STS) for PPS were excluded from the analysis. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier with hazard ratio (HR) obtained via Mantel-Haenszel or log rank. RESULTS: 157 total cases were included, from which 50 cases were PPS and 107 cases CWS. For PPS, 4 cases were excluded from the analysis as they were not true STS. The most common histology was undifferentiated sarcomas, 63% of cases were treated with E/C/I and 37% with another regimen. The E/C/I regimen demonstrated a benefit for both OS (p = 0.020) and PFS (p = 0.010) when compared to any other regimen as well as when compared to non-platinum regimens (p = 0.016 and p = 0.001). Regarding CWS, the most common histology was synovial and undifferentiated sarcomas, 55.1% were treated with E/C/I and 44.9% treated with another regimen. The E/C/I regimen did not demonstrate a benefit for OS or PFS compared to any other regimen, neither when compared to other non-platinum regimens. However, a benefit was observed in favor of E/C/I when compared to other platinum regimens in both OS (p = 0.049) and PFS (0.015). Both analyses for PPS and CWS demonstrated a benefit in favor of cisplatin therapies compared to carboplatin in both OS and PFS. CONCLUSION: This study demonstrates that platinum therapy alone does not work, and that cisplatin must be the agent of choice and it's used in combination could increase treatment response. The E/C/I regimen demonstrated a in PPS but not for CWS, this is due do their rarity of PPS and that no standard treatment is established yet. The regimen proposed here could represent a possible new standard of treatment for PPS as long as it is validated in a prospective study.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Cisplatino , Ifosfamida , Epirubicina , Estudos Retrospectivos , Estudos Prospectivos , Sarcoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The present study investigates the use of UV light and the ozone process for doxorubicin, daunorubicin, epirubicin, and irinotecan degradation. The process was carried out using different pH values in hospital wastewater. The use of UV radiation reduces the concentration of anticancer drugs, but in all cases, this technology was not able enough to remove on the whole these contaminants from hospital wastewater. The best condition was achieved when using pH 9 for most of the analytes. Doxorubicin, daunorubicin, and epirubicin were degraded at 97.3%, 88.3%, and 99.0%, respectively. Irinotecan showed the lowest degradation, just 55.6%; a slightly higher degradation (63.8%) was obtained when pH 5 was used. Complete removal of doxorubicin, daunorubicin, epirubicin, and irinotecan was achieved when ozone treatment was used for all the pH studied. The results indicated that UV light and the ozone process can be used as a tertiary treatment to reduce the concentration of anticancer drugs in the effluents. Ozonation, therefore, proved to be more efficient than the photolysis process, when considering the percentual degradation of the original compounds in shorter timespans.
Assuntos
Antineoplásicos , Ozônio , Poluentes Químicos da Água , Purificação da Água , Epirubicina , Hospitais , Irinotecano , Oxirredução , Ozônio/química , Fotólise , Raios Ultravioleta , Águas Residuárias/química , Poluentes Químicos da Água/química , Purificação da Água/métodosRESUMO
UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan-Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.
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Antibióticos Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Ácido Hialurônico/biossíntese , Neoplasias de Mama Triplo Negativas/enzimologia , Uridina Difosfato Glucose Desidrogenase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Epirubicina/farmacologia , Feminino , Humanos , Prognóstico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Cardiotoxicity is a common and serious adverse effect of anthracycline therapy in breast cancer patients. The current criteria for cardiotoxicity are based on imaging and cardiac biomarkers. However, there is a need for new biomarkers to help with early diagnosis. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression. Several miRNAs have been associated with cardiovascular diseases and are biomarkers under investigation for cancer treatment-related cardiotoxicity. METHODS: We performed a systematic literature search of Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Web of Science and Embase, until April 2020. Cohort studies that reported miRNA biomarkers in breast cancer patients with anthracycline-induced cardiotoxicity and non-cardiotoxicity patients were included. Moreover, we searched the miRTarBase for experimentally validated miRNA-target interactions. RESULTS: Among the 209 studies retrieved, five fulfilled the inclusion criteria. Let-7f, miR-1, miR-20a, miR-126 and miR-210 were validated in two population-based cohorts. The pro-angiogenic miRNAs let-7f, miR-20a, miR-126 and miR-210 were significantly down-regulated in epirubicin-cardiotoxicity when compared to the non-cardiotoxicity group. miR-1 has been shown to provide diagnostic and prognostic information in the setting of myocardial infarction, but changes in its levels are controversial in doxorubicin-treated breast cancer patients with cardiotoxicity. Reactome pathways relevant to cardiotoxicity were found from the target genes for let-7f, miR-1, miR-20a, miR-126 and miR-210 at miRTarBase. CONCLUSION: The data suggest that let-7f, miR-1, miR-20a, miR-126 and miR-210 are associated with anthracycline-based cardiotoxicity during chemotherapy in breast cancer patients.
Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , MicroRNAs/fisiologia , Neoplasias da Mama/genética , Feminino , Humanos , MicroRNAs/sangueRESUMO
Epirubicin is a cytotoxic drug used in the treatment of different types of cancer and increasing evidence suggests that its target is cell membranes. In order to gain insight on its toxic effects, intact red blood cells (RBC), human erythrocyte membranes and molecular models were used. The latter consisted in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes found mainly in the outer and inner monolayers of the human erythrocyte membrane, respectively. The results obtained by X-ray diffraction displayed that epirubicin induced structural perturbations in multilayers of DMPC. Differential scanning calorimetry (DSC) showed that epirubicin disturbed the thermotropic behavior of both DMPC and DMPE vesicles, whereas fluorescence spectroscopy demonstrated alterations in the fluidity of DMPC vesicles and the erythrocyte membrane. Scanning electron microscopy (SEM) revealed that epirubicin changed the normal discoid form of RBC to echinocytes and stomatocytes. Electron paramagnetic resonance (EPR) disclosed that this drug induced conformational changes in the erythrocyte membrane proteins. These findings demonstrate that epirubicin interacts with lipids and proteins of the human erythrocyte membrane, effects that might compromise the integrity and function of cell membranes. This is the first time that its toxic effects on the human erythrocyte membrane have been described.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Epirubicina/toxicidade , Eritrócitos/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Células Cultivadas , Dimiristoilfosfatidilcolina , Eritrócitos/patologia , Eritrócitos/ultraestrutura , Humanos , Lipossomos , Microscopia Eletrônica de Varredura , Fosfatidiletanolaminas , Difração de Raios XRESUMO
Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii Transmission-blocking activity was observed for epirubicin in vitro and in vivo Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.
Assuntos
Antimaláricos , Malária Vivax , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos , Epirubicina/uso terapêutico , Malária Vivax/tratamento farmacológico , Camundongos , Plasmodium falciparum/genética , Plasmodium vivax/genéticaRESUMO
ABSTRACT Propolis is a natural substance, produced by honeybees from the resin of various plants. The purpose of this study was to determine the chemical composition and evaluate the hepatoprotective effect of ethyl acetate extract of propolis from Tigzirt, against the toxicity induced by epirubicin which is a anticancer agent, and belongs to the family of antracyclines. The study included thirty male Wistar albino rats divided into five groups. The rats received the extraction of propolis or the quercetin orally for 15 days. The hepatotoxicity was promoted by injection epirubicin (i.v.) with a cumulative dose of 9 mg/kg. Several biological parameters were measured. Oxidative status was also assessed by evaluating antioxidant enzyme and histological study of some organs. Epirubicin caused oxidative stress by a significant decrease in hepatic antioxidant enzymes (gluthation peroxidase, catalase, superoxide dismutase), increased malondialdehyde and liver parameters (ASAT, ALAT, γGT, ALP) compared to the control. The histological study revealed major damage to the liver. Perturbations in this liver function, antioxidant status and damage to the liver by epirubicin have been repaired by the administration of propolis. Furthermore, epirubicin showed inflammatory effects induced by an increase in TNF-α and PGE2. Pretreatment with propolis to rats restored these inflammatory parameters. The chemical identification of extract of propolis by HPLC/UV shows the presence of polyphenolic compounds and many flavonoids. The propolis extract showed a significant reduction in oxidative damage from oxidative stress and a very important protective effect against epirubicin-induced hepatotoxicity.
RESUMO
OBJECTIVE: To assess the pathological complete response (pCR) rate after neoadjuvant chemotherapy (NC) with anthracyclines with or without taxanes in management of locally advanced breast cancer (LABC). METHOD: Patients with LABC were included. A cohort received four cycles of 5-fluorouracil [FEC] (FEC 500 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 500 mg/m2) every 3 weeks followed by four cycles of docetaxel (D) 75 mg/m2 as 1 h infusion intravenous every 3 weeks. Another cohort received six cycles of FE100C (500, 100 and 600 mg/m2). The chemotherapy was followed by surgery and radiotherapy. RESULTS: There was no statistically significant difference in overall response rate (ORR) (ORR: 78.5 vs. 85%; p = 0.299) and clinical complete response (cCR) (c CR: 20.6 vs. 33.3%; p = 0.103) for 4FECâ4D compared to 6FE100C, respectively. Instead, there was a statistically significant improved rate of pCR (30.2 vs. 16.7%; p = 0.049) and negative axillary lymph nodes (51.6 vs. 35%; p = 0.03) for 4FECâ4D compared to 6FE100C, respectively. Serious toxicity was low and non-significant in both cohorts. The logistic regression multivariate models showed that main significant predictors to obtain a pCR were 4FECâ4D NC (odds ratio [OR]: 2.7; p = 0.019) and stage IIIA (OR: 3.8; p = 0.002). CONCLUSION: This study showed that 4FECâ4D regimen with conventional dose is highly active and well tolerated in patients with LABC in our hospital.
OBJETIVO: Evaluar la tasa de respuesta patológica completa (RPc) posterior a la quimioterapia neoadyuvante (QN) con antraciclinas con o sin taxanos en el manejo del cáncer de mama localmente avanzado (CMLA). MÉTODO: Se incluyeron pacientes con CMLA. Una cohorte recibió cuatro ciclos de FEC (5-fluorouracilo 500 mg/m2, epirubicina 75 mg/m2, ciclofosfamida 500 mg/m2) cada 3 semanas seguido por cuatro ciclos de docetaxel (D) 75 mg/m2 en infusión intravenosa de 1 hora cada 3 semanas. Otra cohorte recibió seis ciclos de FE100C (500, 100 y 600 mg/m2). Se realizó cirugía posterior a la quimioterapia. RESULTADOS: No hubo diferencia estadísticamente significativa en las tasas de respuesta objetiva (78.5 vs. 85.0%; p = 0.299) ni en la respuesta clínica completa (20.6 vs. 33.3%; p = 0.103) para 4FECâ4D comparado con 6FE100C, respectivamente. En cambio, hubo una mejora significativa en la tasa de RPc (30.2 vs. 16.7%; p = 0.049) y en los ganglios linfáticos axilares negativos (51.6 vs. 35%; p = 0.03) para 4FECâ4D en comparación con 6FE100C, respectivamente. La toxicidad grave fue baja y no significativa en ambas cohortes. Los modelos multivariados de regresión logística mostraron que los principales predictores significativos para obtener una RPc fueron la QN con 4FECâ4D (odds ratio [OR]: 2.7; p = 0.019) y el estadio IIIA (OR: 3.8; p = 0.002). CONCLUSIÓN: Este estudio mostró que el régimen 4FECâ4D con dosis convencional es muy activo y bien tolerado en pacientes con CMLA en nuestro hospital.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Coortes , Docetaxel/efeitos adversos , Quimioterapia Combinada , Epirubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background: Gastric cancer is one of the most common malignancies worldwide. Epirubicin (EPI) is used extensively in the treatment of multiple cancers despite its tendency to induce multidrug resistance though overexpression of the ABCB1 efflux pump. However, this overexpression can be disrupted using short interfering RNAs (siRNAs). Objective and Methods: The aim of this study was to explore approaches to reverse EPI resistance and thus increase the success of chemotherapy treatment in an EPI-resistant gastric cancer cell subline (AGS/EPI). Methods: The study focused on effects of ABCB1 knockdown by siRNA technology using TaqMan gene expression assays with quantitative real-time reverse-transcription PCR (qRT-PCR). MTT assays were performed to evaluate viability and prolifer in subline. ABCB1 protein localization and EPI intracellular fluorescence intensity in AGS/EPI cells were detected by confocal microscopy. Results: The siRNA efficiently downregulated ABCB1 mRNA in AGS/EPI cells. Thus MDR reversal was clearly demonstrated in the AGS/EPI cells, offering the possibility of future in vitro chemoresistance assays for the GC field. Conclusions: ABCB1 knockdown decreased EPI efflux and increased EPI sensitivity in AGS/EPI cells. This result provides a novel strategy for targeted gene therapy to reverse EPI resistance in gastric cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Epirubicina/farmacologia , RNA Interferente Pequeno/genética , Neoplasias Gástricas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antibióticos Antineoplásicos/farmacologia , Apoptose , Sobrevivência Celular , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Células Tumorais CultivadasRESUMO
Present work is aimed to develop a simple, sensitive, robust and reliable HPLC method for routine quality control of epirubicin (EPI) in bulk drug, marketed injections and polymeric nanoparticles. Separation was carried out by C18 column. Isocratic elution was carried out using mobile phase A: 0.16% o-phosphoric acid solution, B: acetonitrile and methanol mixture (80:20, v/v) in the ratio of 60:40 (A: B) while the flow rate was maintained at 1mL/min. Analyses were performed at 233.5 nm using PDA detector. Excellent linear relationship was observed between peak-area versus drug concentration in the range of 1.0-100.0 µg/mL (r2, 0.999). Developed method was found to be sensitive (Limits of detection and quantification were found to be ~8 ng/mL and ~25 ng/mL, respectively), precise (RSD <1.0%, for repeatability and <2.0% for intermediate precision, within acceptable ranges of precision), accurate (recovery in different dosage form, 94.65 -100.26%, within acceptable range, 80-120%), specific and robust (% RSD <2, for system suitability parameters). Stress-induced degradation studies demonstrated that method can suitability be applied in the presence of degradants. Developed method has been successfully applied for the determination of entrapment efficiency, drug loading, in vitro release profile, in vitro permeation studies as well as stability assessment of polymeric nanoparticles
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Controle de Qualidade , Epirubicina/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Técnicas In Vitro/instrumentação , Nanopartículas/análiseRESUMO
Cashew gum (CG) was grafted with N-isopropylacrylamide (NIPA) by radical polymerization to originate a stimuli-sensitive copolymer for drug delivery purposes. NMR and IR spectroscopy confirmed the insertion of NIPA onto the cashew gum chains. The graft copolymer (CG:NIPA) demonstrated thermal responsiveness. The critical aggregation concentration of the copolymers at 25°C was higher than at 50°C. At temperatures lower than the LCST, the nanoparticle size ranged from 12 to 21nm, depending on the CG:NIPA ratio, but above the LCST the particles aggregated, increasing the particle size. Regarding the potential for future oral application, the nanoparticles showed no cytotoxic activity against the Caco-2 and HT29-MTX intestine cell lines. Epirubicin was encapsulated into nanoparticles of CG-NIPA (1:1), resulting in a 64% association efficiency and 22% loading capacity. Thus, the CG:NIPA graft copolymer demonstrates good potential for used in controlled drug delivery systems.