Can pumpkin save us of doxorubicin induced cardiotoxicity? / ¿Puede la calabaza salvarnos de la cardiotoxicidad inducida por doxorrubicina?

SUMMARY: Doxorubicin (DOX) is one of the drugs necessary for the treatment of the 10 most common types of cancer. The leading adverse effect limiting clinical use of DOX is cardiotoxicity. Given that literature data indicate a protective role of carotenoids in doxorubicin-induced toxicity, in our study we compared the cardioprotective effect of a mixture of pumpkin carotenoids and a commercially available antioxidant preparation. Animals were distributed in 8 groups (Control - S; NADES - N; Doxorubicin - Dox; Carotenoids - Car; CardiofortIN - CF; NADES-Doxorubicin - N-Dox; Carotenoids-Doxorubicin - Car-Dox; CardiofortIN-Doxorubicin - CF-Dox). Histological sections were stained with the hematoxylin-eosin (HE) and analyzed for the presence of myocardial damage by doxorubicin damage score (DDS). From the heart tissue homogenate were determined the intensity of lipid peroxidation and specific antioxidative enzyme activity (superoxide dismutase; catalase; glutathione S-transferase; glutathione peroxidase). In Car-DOX and CF-DOX groups, lipid peroxidation is significantly reduced compared to DOX group. Pretreatment of animals with carotenoids and in lesser extent with CardiofortIN led to higher antioxidative enzymes activity, compared to DOX group. Pretreated with carotenoids, only 50 % of animals had some degree of myocardial damage, and no animals had extensive damage. CardiofortIN pretreatment showed less protective effect. Pretreatment with carotenoid extract, reduced DDS significantly, so Car-DOX group has changes equivalent to mild myocardial damage. Although CardiofortIN pretreatment lowered DDS score values, animals still had moderate level of myocardium damage. This in vivo study and its findings indicate that carotenoids extracted from pumpkin may be a promising cardioprotective agent against doxorubicin induced cardiotoxicity, at least in part mediated through inhibition of DOX-induced oxidative stress.

La doxorrubicina (DOX) es uno de los fármacos necesarios para el tratamiento de los 10 tipos más comunes de cáncer. El principal efecto adverso que limita el uso clínico de DOX es la cardiotoxicidad. Debido a que los datos de la literatura indican un papel protector de los carotenoides en la toxicidad inducida por doxorrubicina, en nuestro estudio comparamos el efecto cardioprotector de una mezcla de carotenoides de calabaza y una preparación antioxidante disponible comercialmente. Los animales se distribuyeron en 8 grupos (Control - S; NADES - N; Doxorrubicina - Dox; Carotenoides - Car; CardiofortIN - CF; NADES-Doxorrubicina - N-Dox; Carotenoides-Doxorrubicina - Car-Dox; CardiofortIN- Doxorrubicina - CF-Dox). Las secciones histológicas se tiñeron con hematoxilina-eosina (HE) y se analizaron para detectar la presencia de daño miocárdico mediante la puntuación de daño por doxorrubicina (DDS). A partir del homogeneizado de tejido cardíaco se determinó la intensidad de la peroxidación lipídica y la actividad enzimática antioxidante específica (superóxido dismutasa, catalasa, glutatión S-transferasa, glutatión peroxidasa). En los grupos Car-DOX y CF-DOX, la peroxidación lipídica se redujo significativamente en comparación con el grupo DOX. El pre tratamiento de los animales con carotenoides y, en menor medida, con CardiofortlN condujo a una mayor actividad de las enzimas antioxidantes, en comparación con el grupo DOX. Al ser pre tratados con carotenoides, solo el 50 % de los animales tenían algún grado de daño miocárdico y ningún animal tenía daño extenso. El pre tratamiento con CardiofortIN mostró un efecto protector menor. El pre tratamiento con extracto de carotenoides redujo significativamente el DDS, por lo que el grupo Car-DOX mostró cambios equivalentes a un daño miocárdico leve. Aunque el pre tratamiento con CardiofortIN redujo los valores de la puntuación DDS, los animales aún tenían un nivel moderado de daño al miocardio. Este estudio in vivo y sus hallazgos indican que los carotenoides extraídos de la calabaza pueden ser un agente cardioprotector prometedor contra la cardiotoxicidad inducida por doxorrubicina, al menos en parte mediada por la inhibición del estrés oxidativo inducido por DOX.

Astragalus polysaccharides affects multidrug resistance gene 1 and P-glycoprotein 170 in adriamycin nephropathy rats via regulating microRNA-16/NF-κB axis / 中南大学学报(医学版)

OBJECTIVES@#Nephrotic syndrome is a common disease of the urinary system. The aim of this study is to explore the effect of astragalus polysaccharides (APS) on multidrug resistance gene 1 (MDR1) and P-glycoprotein 170 (P-gp170) in adriamycin nephropathy rats and the underlying mechanisms.@*METHODS@#A total of 72 male Wistar rats were divided into a control group, a model group, an APS low-dose group, an APS high-dose group, an APS+micro RNA (miR)-16 antagomir group and an APS+miR-16 antagomir control group, with 12 rats in each group. Urine protein (UP) was detected by urine analyzer, and serum cholesterol (CHOL), albumin (ALB), blood urea nitrogen (BUN), and creatinine (SCr) were detected by automatic biochemical analyzer; serum interleukin-6 (IL-6), IL-1β, tumor necrosis factor α (TNF-α) levels were detected by ELISA kit; the morphological changes of kidney tissues were observed by HE staining; the levels of miR-16 and MDR1 mRNA in kidney tissues were detected by real-time RT-PCR; the expression levels of NF-κB p65, p-NF-κB p65, and P-gp170 protein in kidney tissues were detected by Western blotting; and dual luciferase was used to verify the relationship between miR-16 and NF-κB.@*RESULTS@#The renal tissue structure of rats in the control group was normal without inflammatory cell infiltration. The renal glomeruli of rats in the model group were mildly congested, capillary stenosis or occlusion, and inflammatory cell infiltration was obvious. The rats in the low-dose and high-dose APS groups had no obvious glomerular congestion, the proliferation of mesangial cells was significantly reduced, and the inflammatory cells were reduced. Compared with the high-dose APS group and the APS+miR-16 antagomir control group, there were more severe renal tissue structure damages in the APS + miR-16 antagomir group. Compared with the control group, the levels of UP, CHOL, BUN, SCr, IL-6, IL-1β, TNF-α, and MDR1 mRNA, and the protein levels of p-NF-κB p65 and P-gp170 in the model group were significantly increased (all P<0.05); the levels of ALB and miR-16 were significantly decreased (both P<0.05). Compared with the model group, the levels of UP, CHOL, BUN, SCr, IL-6, IL-1β, TNF-α, and MDR1 mRNA, and the protein levels of pNF-κB p65 and P-gp170 in the low-dose and high-dose APS groups were significant decreased (all P<0.05); and the levels of ALB and miR-16 were significantly increased (both P<0.05). Compared with APS+miR-16 antagomir control group, the UP, CHOL, BUN, SCr, IL-6, IL-1β, and TNF-α levels, MDR1 mRNA, and the protein levels of p-NF-κB p65 and P-gp170 were significantly increased (all P<0.05). The levels of ALB and miR-16 were significantly decreased in the APS+miR-16 antagomir group compared with the APS+miR-16 antagomir control group (both P<0.05).@*CONCLUSIONS@#APS can regulate the miR-16/NF-κB signaling pathway, thereby affecting the levels of MDR1 and P-gp170, and reducing the inflammation in the kidney tissues in the adriamycin nephropathy rats.

Is paclitaxel less cardiotoxic in the treatment of breast cancer before or after doxorubicin? / Qual estratégia terapêutica é menos cardiotóxica no tratamento do câncer de mama: uso de paclitaxel antes ou depois da doxorrubicina?

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) effectively treats breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. Consensus is lacking about which drug sequence involves the most CTX. Objectives: To evaluate whether DOX followed by PXT or the reverse sequence has the greatest cardiotoxic potential in the treatment of BC. Methods: Prospective study of women with primary BC who received four cycles of DOX and 12 infusions of PTX. Participants were divided into Group 1 (G1; PXT before DOX) and Group 2 (G2; DOX before PXT) at the discretion of the oncologist. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF) > 10% to a value <53%. Patients underwentclinical evaluations and echocardiography before treatment (Phase 1) and one year after treatment (Phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX, and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). The mean LVEF was similar between groups in Phase 1 (G1=65.1±3.5%; G2=65.2±3.9%; p=0.96), with a significant reduction noted after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0,001). Although lower, mean LVEF remained similar between groups after Phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. (AU)

Efeito Cardioprotetor da Suplementação Materna com Resveratrol sobre a Toxicidade Induzida por Doxorrubicina em Cardiomiócitos de Neonatos / Cardioprotective Effect of Maternal Supplementation with Resveratrol on Toxicity Induced by Doxorubicin in Offspring Cardiomyocytes

Resumo Fundamento A doxorrubicina (DOX) é frequentemente usada para tratar muitos tipos de cânceres, apesar da cardiotoxicidade dose-dependente. Como alternativa, o resveratrol é um polifenol que tem demonstrado efeitos cardioprotetores em vários modelos de disfunção cardíaca. Objetivo Este estudo investigou se o tratamento com resveratrol em ratas gestantes protege contra toxicidade induzida por doxorrubicina em cardiomiócitos da ninhada. Métodos Ratas Wistar (n-8) receberam sresveratrol como suplemento alimentar durante a gestação. No nascimento da ninhada, os corações (9-11) foram usados para se obter a cultura primária de cardiomiócitos. A cardiotoxicidade induzida por DOX e os efeitos da suplementação com resveratrol foram avaliados por marcadores de stress oxidativo, tais como oxidação da diclorofluoresceína diacetato, diminuição da atividade de enzimas antioxidantes, e oxidação do teor total de grupos sulfidrila, além da avaliação da viabilidade celular, geração de danos ao DNA, bem como a resposta de reparo aos danos ao DNA. Um valor de p <0,05 foi considerado estatisticamente significativo. Resultados Os cardiomiócitos de neonatos de ratas que receberam suplemento resveratrol apresentaram um aumento (p <0,01) na viabilidade das células, e diminuição (p <0,0001) de células apoptóticas/necróticas após o tratamento com DOX, o que está correlacionado às atividades de enzimas antioxidantes e produção de diclorofluoresceína. Além disso, o resveratrol protegeu os cardiomiócitos de danos ao DNA induzidos por DOX, apresentando uma diminuição (p <0,05) nas quebras de DNA induzidas por stress oxidativo, avaliadas pela atividade de enzimas reparadoras do DNA endonuclease III e formamidopirimidina glicosilase. A suplementação com resveratrol aumentou (p <0,05) a expressão da proteína reparadora Sirt6 nos cardiomiócitos dos filhotes. Conclusão Essa pesquisa indica que a suplementação com resveratrol durante o período gestacional tem um efeito cardioprotetor no coração da ninhada contra a toxicidade induzida por DOX, o que pode se dever a sua função antioxidante, e o aumento na resposta de danos ao DNA.

Abstract Background Doxorubicin (DOX) is frequently used to treat many types of cancers, despite its dose-dependent cardiotoxicity. Alternatively, resveratrol is a polyphenol that has shown useful cardioprotective effects in many heart dysfunction models. Objective This study investigated whether resveratrol treatment in pregnant rats protects against doxorubicin-induced toxicity in offspring cardiomyocytes. Methods Wistar rats (n=8) were supplemented with dietary resveratrol during pregnancy. Upon the offspring's birth, hearts (9-11) were used to obtain the primary culture of cardiomyocytes. DOX-induced cardiotoxicity and the effects of resveratrol supplementation were evaluated by oxidative stress markers, such as dichlorofluorescein diacetate oxidation, decrease in the activity of antioxidant enzymes, and oxidation of total sulfhydryl content, in addition to cell viability evaluation, DNA damage generation, and DNA damage repair response. A value of p<0.05 was considered statistically significant. Results Neonatal cardiomyocytes from resveratrol supplemented rats exhibiting an increase (p<0.01) in cell viability and lower (p<0.0001) apoptotic/necrotic cells after DOX treatment, which correlates with the activities of antioxidant enzymes and dichlorofluorescein production. Moreover, resveratrol protected cardiomyocytes from DOX-induced DNA damage, showing a decrease (p<0.05) in DNA breaks induced by oxidative stress, evaluated by the activity of DNA-repair enzymes endonuclease III and formamidopyrimidine glycosylase. Supplementation with resveratrol increased (p<0.05) the expression of the repair protein Sirt6 in the cardiomyocytes of the pups. Conclusion This research indicates that supplementation with resveratrol during the gestational period has a notable cardioprotective effect on the offspring's heart against DOX-induced toxicity, which may well be due to its antioxidant function, and the increase in the DNA damage repair response.

Protective Effect of Rosa Canina Extract Against Doxorubicin-induced Testicular Toxicity in Mice

Abstract The present study was aimed to investigate the in vivo effects of Rosa canina extract on doxorubicin-induced testicular toxicity in mice for the first time. Male NMRI mice were randomly divided into six treatment groups (10=per group) as follows: (I) vehicles, (II) doxorubicin alone (3 mg/kg, i.p. on days 7, 14 and 21), (III and IV): Rosa canina extract alone (100 mg/kg and 200 mg/kg per day, i.p. for 28 days), (V and VI) Rosa canina extract plus doxorubicin (each dose given 1 h post Rosa canina). Doxorubicin-treated mice displayed smaller body and testicular weights, decreased serum levels of testosterone, loss in the number of germ cells and Sertoli cells, and reduced sperm count, viability, morphology and motility. Doxorubicin treatment significantly decreased the mean testis diameter, seminiferous tubular diameter and seminiferous epithelial height and increased seminiferous luminal diameter. However, Rosa canina pretreatment could effectively improve all of these abnormalities in doxorubicin- treated mice. The treatment with a higher dose of the extract (200 mg/kg) was more effective compared to doxorubicin and the lower dose of the extract. These findings suggested that the Rosa canina extract has protective effects against doxorubicin-induced reproductive toxicity.

Mesenchymal stem cells reduce left ventricular mass in rats with doxorubicin-induced cardiomyopathy / Las células madre mesenquimales reducen la masa ventricular izquierda en ratas con miocardiopatía inducida por doxorrubicina

SUMMARY: Doxorubicin is a drug that used by a majority in the treatment of carcinomas. The most obvious known side effect is cardiomyopathy. Many studies have been carried out to eliminate side effects of the doxorubicin, and stem cell studies have been added in recent years. In this study, it was aimed to investigate fetal-derived mesenchymal stem cells (F-MSCs) treatment of doxorubicininduced cardiomyopathy by morphological methods. A total of 24 rats which were divided into three separate groups (Control, sham, treatment), each consisting of 8 male rats were used. In sham and treatment group, Adriamycin was administered in a single dose by tail injection to perform cardiotoxicity. In the treatment group, F-MSCs were intra-peritoneally administrated. Then, rats were euthanized and their hearts were photographed at the level of papillary muscle. and thickness, diameters and surface area levels were measured. Left ventricular mass (LVM) and left ventricular mass index (LVMI) were calculated after measurement. The sham group, LVM and LVMI levels were found to significantly lower (p<0.05) than control and treatment group. In the one hand, LVMI levels of rats in treatment group was statistically similar (p>0.05) to control group. Similarly, LVM levels of control and treatment groups were close to each other while this level of sham group was lower. It has been shown that F-MSC administrations in rats with doxorubicin-induced cardiomyopathy have adverse effect on LVM and LVMI values. In addition, the intra-peritoneal MSC administrations may be an alternative to other injection routes such as intra-venous and intra-cardiac administrations.

RESUMEN: La doxorrubicina es un medicamento usado ampliamente en el tratamiento de carcinomas. El efecto secundario más conocido es la miocardiopatía. Se han llevado a cabo muchos estudios para eliminar los efectos secundarios de la doxorrubicina, y en los últimos años se han agregado estudios con células madre. mediante métodos morfológicos, se intentó investigar el tratamiento de las células madre mesenquimales (F-MSCs) derivadas del feto, de la miocardiopatía inducida por doxorrubicina. Se utilizó un total de 24 ratas que se dividieron en tres grupos (control, simulación, tratamiento), cada uno de las cuales consistía en 8 ratas macho. En el tratamiento simulado y en el grupo tratamiento, se administró doxorrubicina en una dosis única mediante inyección en la cola de la rata para realizar cardiotoxicidad. En el grupo tratamiento, las FMSC se administraron intraperitonealmente. Luego, las ratas fueron sacrificadas y sus corazones fueron fotografiados a nivel de los músculos papilares, y se midieron los espesores, los diámetros y los niveles de área superficial. Después de las mediciones se calcularon la masa ventricular izquierda (MVI) y el índice de masa ventricular izquierda (IMVI). En el grupo simulado, los niveles de MVI y IMVI se encontraron significativamente inferiores (p <0.05) que en los grupos control y tratamiento. Por un lado, los niveles de IMVI de las ratas en el grupo de tratamiento fueron estadísticamente similares (p> 0,05) al grupo de control. De forma similar, los niveles de MVI de los grupos control y tratamiento se aproximaban uno al otro, mientras que este nivel era más bajo en el grupo simulado. Se ha demostrado que la administracion de F-MSC en ratas con miocardiopatía inducida por doxorrubicina tiene un efecto adverso sobre los valores de MVI y IMVI. Además, la administracion de MSC intraperitoneal puede ser una alternativa a otras rutas de inyección tal como las administración intravenosa e intracardíaca.

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy / Metaloproteinases de matriz 2 e 9 em coelhos com cardiomiopatia induzida pela doxorrubicina

Some studies have shown the role played by matrix metalloproteinases and their inhibitors in doxorubicin cardiotoxicity. In this study, we sought to investigate how plasma and myocardial MMP 2 and 9 perform in rabbits with doxorubicin-induced cardiomyopathy, searching for a correlation between the activity of these collagenases and cardiac remodeling. Cardiomyopathy was induced by doxorubicin given intravenously twice a week for six consecutive weeks. Plasma MMP activity and the echocardiogram were assessed at baseline, and at 15 and 45 days after first injection of doxorubicin. The myocardial activity of these enzymes was solely evaluated in nine rabbits at 45 days, and results were compared with nine healthy controls. We only identified the full-length forms of both MMP 2 and 9 throughout the study. The plasma pro-MMP 2 reduced along the deterioration of cardiac function, while the pro-MMP 9 increased significantly at T45 as compared to baseline and T15. A negative significant correlation was found to exist between the plasma activity of pro-MMP 2 and mitral E-to-mitral septal annular early diastolic velocity ratio, which is an estimate of mean left atrial pressure and congestion. Only pro-MMP 2 was found in myocardial samples, and mean activity of such enzyme was statistically lower than that recorded for healthy controls. Although no active form was documented for either collagenase, the duration of the treatment with doxorubicin played a role in the alteration of plasma pro-forms activity. However, these changes could not be associated with most echocardiographic parameters that are supportive of cardiac remodeling.(AU)

Alguns estudos já demonstraram o papel exercido pelas metaloproteinases de matriz e seus inibidores na cardiotoxicidade promovida pela doxorrubicina. Assim, este estudo teve como objetivo investigar o comportamento das MMPs 2 e 9 plasmáticas e miocárdicas em coelhos com cardiomiopatia induzida pela doxorrubicina, buscando determinar se há correlação entre a atividade dessas colagenases e o remodelamento cardíaco. A cardiomiopatia foi induzida pela doxorrubicina aplicada por via intravenosa duas vezes por semana ao longo de seis semanas consecutivas. A atividade plasmática das MMPs e o ecocardiograma foram avaliados no momento basal e aos 15 e 45 dias após a primeira aplicação da doxorrubicina. A atividade miocárdica dessas enzimas foi quantificada em apenas nove coelhos aos 45 dias e os resultados comparados com outros nove controles saudáveis. Foram identificadas apenas as formas inativas das MMPs 2 e 9 durante todo o estudo. A pro-MMP 2 plasmática reduziu à medida que a função cardiaca se deteriorou, enquanto a pro-MMP 9 aumentou significativamente em T45 quando comparada aos momentos basal e T15. Houve correlação negativa significativa entre a atividade plasmática da pro-MMP 2 e a relação entre E mitral e a velocidade anular mitral no início da diástole, um parâmetro que permite estimar a pressão atrial esquerda média e a congestão. Apenas a pro-MMP 2 foi documentada nas amostras miocárdicas dos coelhos com cardiomiopatia e atividade media dessa enzima foi estatisticamente menor que aquela observada nos controles saudáveis. Embora a forma ativa de ambas as colagenases não tenha sido identificada, o tempo de tratamento com doxorrubicina interferiu na atividade das formas inativas plasmáticas. Contudo, essas alterações não se associaram com a maioria dos parâmetros ecocardiográficos que indicam remodelamento cardíaco.(AU)

Reduction of doxorubicin-induced genotoxicity by Handroanthus impetiginosus in mouse bone marrow revealed by micronucleus assay / Redução da genotoxicidade induzida pela doxorrubicina por Handroanthus impetiginosus na medula óssea de camundongos revelada pelo ensaio do micronúcleo

Abstract Handroanthus impetiginosus has long been used in traditional medicine and various studies have determined the presence of bioactive chemical compounds and potential phytotherapeutics. In this study, the genotoxicity of the lyophilized tincture of H. impetiginosus bark (THI) was evaluated in mouse bone marrow using micronucleus assays. The interaction between THI and genotoxic effects induced by the chemotherapeutic agent, doxorubicin (DXR), was also analyzed. Experimental groups were evaluated 24 to 48 h after treatment with N-nitroso-N-ethylurea (NEU; 50 mg/kg), DXR (5 mg/kg), sodium chloride (NaCl; 150 mM), and THI (0.5-2 g/kg). Antigenotoxic assays were carried out using THI (0.5 g/kg) in combination with NEU or DXR. Analysis of the micronucleated polychromatic erythrocytes (MNPCEs) indicated no significant differences between treatment doses of THI (0.5-2 g/kg) and NaCl. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios did not indicate any statistical differences between DXR and THI or NaCl, but there were differences between THI and NaCl. A significant reduction in MNPCEs and PCE/NCE ratios was observed when THI was administered in combination with DXR. This study suggested the absence of THI genotoxicity that was dose-, time-, and gender-independent and the presence of moderate systemic toxicity that was dose-independent, but time- and gender-dependent. The combination of THI and DXR also suggested antigenotoxic effects, indicating that THI reduced genotoxic effects induced by chemotherapeutic agents.

Resumo Handroanthus impetiginosus tem sido usada durante um longo período pela medicina tradicional e vários estudos têm demonstrados a presença de compostos químicos e potencial fitoterapêutico. Esta pesquisa avaliou a genotoxicidade da tintura da casca liofilizada de H. impetiginosus (THI) usando o ensaio do micronúcleo em medula óssea de camundongos. A interação entre THI e os efeitos genotóxicos induzidos pelo quimioterápico doxorrubicina (DXR) também foram analisados. Grupos experimentais foram analisados a 24-48 h após o tratamento com N-Nitroso-N-etiluréia (NEU; 50 mg/kg), DXR (5 mg/kg), NaCl (150 mM) e THI (0,5-2 g/kg). O ensaio antigenotóxico foi conduzido utilizando THI (0,5 g/kg) em combinação com NEU ou DXR. A análise de eritrócitos policromáticos micronucleados (EPCMNs) não mostrou diferenças significativas entre as doses de tratamento (0,5-2 g/kg) e NaCl. As proporções de eritrócitos policromáticos (EPC)/eritrócitos normocromáticos (ENC) não revelaram diferenças estatísticas entre DXR e THI ou NaCl, porém houve diferenças entre THI e NaCl. Uma redução significativa em EPCMNs e na razão EPC/ENC foi observada quando THI foi administrado em combinação com DXR. Essa pesquisa sugere ausência de genotoxicidade de THI, dose-, tempo- e sexo-independente, e moderada toxicidade sistêmica dose-independente, mas tempo- e sexo-dependente. A associação do THI e DXR também sugere efeitos antigenotóxicos. Por conseguinte, THI pode reduzir os efeitos genotóxicos induzidos pelo quimioterapêutico.

Ação do extrato etanólico da casca do pequi (Caryocar brasiliense) na cardiotoxicidade crônica induzida por doxorrubicina em ratos / Caryocar brasiliense shell ethanol extract in chronic cardiotoxicity induced by doxorubicin in rats

A doxorrubicina (DOX) é um quimioterápico utilizado no tratamento de neoplasias malignas, porém possui a cardiotoxicidade como efeito colateral. O objetivo deste trabalho foi verificar quanto à ação do extrato etanólico da casca do pequi (Caryocar brasiliense) (EECP) por meio de avaliação morfológica (macroscópica, microscópica e ultramicroscópica), bem como avaliar a expressão de metaloproteinases (MMP2 e MMP9) e seus inibidores teciduais (TIMP1 e TIMP2) no miocárdio de ratos submetidos à cardiotoxicidade crônica pela DOX, tratados ou não com o EECP. O experimento teve duração de três meses e foram utilizados 30 ratos da raça Wistar, distribuídos em seis grupos de cinco animais. G1 e G2 receberam como pré-tratamento 300mg/kg e 600mg/kg de EECP, respectivamente, por gavagem, durante sete dias e mantiveram o tratamento durante os 21 dias de aplicação da DOX. Em G1, G2, G3, G4 e GC, a cardiotoxicidade foi induzida com aplicações semanais de 2mg/kg de DOX, via intraperitoneal, totalizando quatro aplicações (8mg/kg) e, nos ratos do grupo Sham (GS), foi aplicado 1ml de solução fisiológica. Os animais do G3 receberam diariamente 300mg/kg e os do G4 600mg/kg de EECP, por gavagem, durante os 21 dias de aplicação da DOX. Os do GC e GS receberam 1 ml de água, diariamente, também por gavagem. Após o término das aplicações, os animais foram mantidos por dois meses, totalizando três meses de experimento. A avaliação macroscópica foi realizada após 90 dias, momento em que foram colhidas amostras para análise em microscopia eletrônica, histopatologia e imunoistoquímica. Ao exame necroscópico foi observada ascite nos animais que receberam DOX. Houve baixo índice de mortalidade (3,33%), representado pela morte de um rato que desenvolveu pneumonia por falsa via. Não foi observada alteração no peso e nas medidas do coração dos ratos. Nas doses de 300 e 600mg/kg, o EECP atenuou a degeneração vacuolar miocítica. Na dose de 600mg/kg, o EECP reduziu a quantidade de células de Anitschkow e a fragmentação das miofibrilas. Não houve resultado significativo quanto à imunomarcação das MMP e, quanto a seus inibidores (TIMP), houve maior imunomarcação de TIMP2 no GC, grupo que recebeu apenas DOX. Concluiu-se que o extrato etanólico da casca do pequi (EECP) é eficiente em minimizar os efeitos da cardiotoxicidade crônica induzida pela DOX no miocárdio de ratos, considerando que nas doses de 300 e 600mg/kg o EECP atenua a degeneração vacuolar miocítica e, na dose de 600mg/kg, o EECP reduz a quantidade de células de Anitschkow e a fragmentação das miofibrilas.(AU)

Doxorubicin (DOX) is a chemotherapic drug used in the treatment of malignancies, but has the cardiotoxicity as collateral effect. The objective of this study was to evaluate the action of pequi shell etanolic extract (Caryocar brasiliense) (PSEE) through morphological evaluation (macroscopic, microscopic and ultramicroscopic), and to evaluate the expression of metalloproteinases (MMP2 and MMP9) and its tissue inhibitors (TIMP1 and TIMP2) in the myocardium of rats with chronic cardiotoxicity by DOX and treated or not with PSEE. The experiment lasted three months and 30 Wistar rats were divided into six groups of five animals. G1 and G2 received 300mg/kg and 600mg/kg of PSEE, respectively, as pretreatment, by gavage for seven days and continued treatment for 21 days of application of DOX. In G1, G2, G3, G4 and GC, cardiotoxicity was induced with weekly applications of 2mg/kg DOX, intraperitoneally, totaling four applications (8 mg/kg), and in the Sham group (GS) 1ml of saline solution was applied. G3 animals received daily 300mg/kg of PSEE, and G4, 600mg/kg, by gavage, for 21 days of application of DOX. The GC and GS received 1ml of water daily by gavage also. After the completion of the application, the animals were kept for two months, with three months of experiment. Macroscopic evaluation was performed after 90 days, at which time samples were taken for analysis in electron microscopy, histopathology and immunohistochemistry. At necropsy, ascites was observed in animals that received DOX. There was a low mortality rate (3.33%), being one mouse that developed false road pneumonia. There was no change in weights and measures of the rat hearts. At doses of 300 and 600mg/kg, the PSEE attenuates myocyte vacuolar degeneration. At a dose of 600mg/kg, PSEE reduces amount Anitschkow cells. There was no significant result on the immunostaining of MMP, but considering their inhibitors (TIMP) there was a greater immunostaining of TIMP2 in GC, the group that received only DOX. It was concluded that PSEE is effective in minimizing effects of chronic cardiotoxicity induced by DOX in the myocardium of rats, whereas at doses of 300 and 600mg/kg, PSEE attenuates vacuolar degeneration in myocytes and at the dose of 600mg/kg the PSEE reduces the amount of Anitschkow cells and myofibrils fragmentation.(AU)

Efeito da Astrocaryum aculeatum (Tucumã) na toxicidade da Doxorrubicina: modelo experimental in vivo / Effect of Astrocaryum aculeatum (tucumã) on doxorubicin toxicity: in vivo experimental model

Resumo Objetivo Obter o óleo do Astrocaryum aculeatum (A.a) e avaliar a genotoxidade/antigenotoxidade pelo teste do micronúcleo em células do sangue periférico. Métodos O óleo da A.a foi obtido por prensagem hidráulica. Os animais foram camundongos Swiss, machos e saudáveis com 6-7 semanas de idade, 6 por grupo. Teste genotóxico e antigenotóxico as concentrações foram de 500, 1.000 e 2.000 mg/kg por 0,5 mL (via oral), seguidas ou não de injeção intraperitoneal de doxorrubicina (0,3mL - 15 mg/kg por peso corporal), além do grupo negativo (água) e dimetilsufóxido (600 µL). As amostras de sangue periférico foram coletadas 24h e 48h após o tratamento. Resultados Houve redução estatisticamente significativa na frequência de micronúcleos em células policromáticas que variou de 34,72% à 38,19% para os tratamentos de 24h, e de 63,70 à 66,12% para os de 48h. Conclusão O óleo fixo do tucumã apresentou potencial antigenotóxico para as concentrações em tratamentos agudos.

Abstract Objective To obtain the oil of Astrocaryum aculeatum (A.a), and evaluate its genotoxicity/antigenotoxicity activities using the micronucleus test in peripheral blood cells. Methods The oil of Astrocaryum aculeatum was obtained by hydraulic pressing. The animals used were healthy Swiss male mice, at 6-7 weeks of age; there were six per group. The genotoxic and antigenotoxic activity of concentrations were 500, 1,000 and 2,000 mg/kg per 0.5 mL (oral), followed or not followed by intraperitoneal injection of doxorubicin (0.3 mL-15 mg/kg by body weight), in addition to a negative group (water) and dimethyl sulfoxide (600 μL). Peripheral blood samples were collected 24h and 48h after treatment. Results A statistically significant reduction was identified in the frequency of micronuclei in polychromatic cells ranging from 34.72% to 38.19% for 24-hour treatments, and from 63.70% to 66.12% for 48 hour. Conclusion The fixed oil of tucumã presented antigenotoxic potential for the concentrations used in acute treatments.

[ protective effect of ethanol extract of ginger [Zingiber officinale] on spermatogenesis toxicity induced by doxorubicin]

Background: DOX is one of the most common drugs used to treat different types of cancer, including testicular cancer. The aim of this study was to evaluate the effect of ethanol extract of ginger on spermatogenesis in rats

Materials and methods: In this experimental study, 56 male rats Wistar were randomly divided into 6 groups of 8 animals control, the sham and experimental group 1 receiving doxorubicin [mg/kg.bw 3] experimental 2 and 3 receiving ginger extract [500, 1000 mg/ kg. bw ] and experimental 4 and 5 received a ginger extract [500, 1000 mg/ kg. bw ] + doxorubicin. The rats were fed extract daily, one hour after doxorubicin injection, for four weeks. DOX [3mg/kg] was administered once a week intraperitoneally. Some sperm parameters, such as the number, viability, morphology and mobility were examined using Eosin-Ngrozin staining

Results: A significant decrease in body weight, sperm count, sperm motility, viability was observed in drug-DOX-treated rats compared with the control group. The reduction in the group treated with DOX with ginger 500 and 1000 mg/ kg significantly was offset compared with DOX

Conclusion: Ginger is able to have protective effect on sperm parameters in adult male rat induced by Doxorobicin

Estudo do efeito do Mito-TEMPO e do ácido lipoico sobre a cardiotoxicidade da dexorrubicina / Study of the effect of weather and Mito-lipoic acid on cardiotoxicity dexorrubicina

Introdução: A doxorrubicina (DOX) é um quimioterápico antracíclico amplamente usado para o tratamento de diversos tumores humanos, entretanto, o desenvolvimento de reações adversas à droga, em particular, cardiotoxicidade, tem limitado seu uso. Embora a toxicidade cardíaca induzida pela DOX pareça ser multifatorial, a hipótese mais investigada tem sido a formação de espécies reativas de oxigênio (ROS) e há evidências apontando para as mitocôndrias cardíacas como alvos primários da toxicidade da DOX. Esse dano oxidativo pode iniciar peroxidação lipídica e pode ser potencialmente limitado pelo uso de antioxidantes. Objetivo: O objetivo do presente estudo foi avaliar a possível eficácia do ácido lipoico (AL) e do Mito-TEMPO (Mito-T) como agentes protetores contra a cardiotoxicidade induzida pela DOX in vitro e in vivo e investigar se essa proteção pode afetar a atividade antitumoral da DOX. Método e Resultados: A capacidade do AL e Mito-T eliminar radicais livres foi avaliada usando o teste do 2,2-difenil-1-picril-hidrazila (DPPH). Menor atividade antioxidante do AL (29%) comparada ao Mito-T (63%) foi observada. DOX reduziu a viabilidade de células H9c2 (CI50 = 40,83 M, IC 95% = 28,64 – 58,21 M) e aumentou a concentração de malondialdeído (MLDA), um marcador de peroxidação lipídica, confirmando a citotoxicidade induzida pela DOX in vitro. O pré-tratamento com AL ou Mito-T não promoveu proteção contra o dano induzido pela DOX in vitro. Uma única injeção intraperitoneal (i.p.) de DOX (24 mg/kg de peso corpóreo) induziu redução significante no peso corpóreo (p<0,001), elevação da atividade sérica total de creatina quinase (p<0,05) e creatina quinase-MB (p<0,05), aumento na concentração de malondialdeído em mitocôndrias (p<0,05) e tecido cardíaco (p<0,01) em camundongos da linhagem C57BL/6 após 48 horas. O pré-tratamento dos animais com Mito-T (5 mg/kg de peso corpóreo, i.p., por dois dias, 48 e 24 horas antes da DOX) reduziu significativamente a peroxidação lipídica de mitocôndrias cardíacas (p<0,01) indicando o direcionamento do antioxidante para a mitocôndria. O tratamento com Mito-T ou AL, duas vezes, 24 e uma hora antes do tratamento com DOX, inibiu a atividade sérica de creatina quinase total (p<0,05). Além disso, o tratamento de camundongos apresentando tumor B16F10 com AL não interferiu na eficácia antitumoral da DOX. Conclusão: Os dados sugerem que a combinação de AL com DOX pode ser benéfica para o tratamento de câncer, entretanto, são necessárias novas investigações para confirmar essa suposição.

Introduction: Doxorubicin (DOX) is an anthracycline chemotherapeutic that is widely used for the treatment of many human tumours, however, the development of adverse drug reactions in particular cardiotoxicity has limited its use. Although doxorubicin-induced cardiac toxicity appears to be multifactorial, the most thoroughly investigated hypothesis has been the formation of reactive oxygen species (ROS) and there is evidence pointing to cardiac mitochondria as primary targets of the toxicity of DOX. This oxidative injury can initiate lipidic peroxidation and may be potentially limited by the use of antioxidants. Aim: The aim of the present study was to evaluate the possible efficacy of lipoic acid (LA) and Mito-TEMPO (Mito-T) as a protective agent against DOX-induced cardiotoxicity in vitro and in vivo and to investigate whether this protection may affect the antitumor activity of DOX. Method and Results: Free radical scavenging capacity of LA and Mito-T was assayed using 1,1-diphenyl-2-picrylhydrazy (DPPH) assay. Lower antioxidant activity for LA (29%) compared to Mito-T (63%) were observed. DOX reduced H9c2 viability (IC50 = 40.83 M, 95% CI = 28.64 – 58.21 M) and increased the levels of malondialdehyde (MLDA), a marker of lipid peroxidation, confirming DOX-induced cytotoxicity in vitro. Pretreatment with LA or Mito-T did not provide protection against DOX-induced damage in vitro. A single intraperitoneal (i.p.) injection of DOX (24 mg/kg body weight) induced a significant reduction in body weight (p<0.001), elevation of serum activity of total creatine kinase (p<0.05) and creatine kinase-MB (p<0.05), increase in malondialdehyde levels in cardiac mitochondria (p<0.05) and cardiac tissue (p<0.01) in C57BL/6 mice after 48 hours...

A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats

Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

Phytomodulatory potential of lycopene from Lycopersicum esculentum against doxorubicin induced nephrotoxicity.

An elevated level of serum urea and creatinine was observed in doxorubicin (DOX) treated animals indicating DOX-induced nephrotoxicity. Enhanced lipid peroxidation (LPO) in the renal tissue was accompanied by a significant decrease in the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) activities. Administration of lycopene (LycT) extracted from tomato to DOX treated mice showed a significant reduction in serum creatinine and urea levels which were associated with significantly low levels of LPO and significantly enhanced level of GSH and related antioxidant enzymes activity (GPx, GR and CAT) when compared to DOX group. Histopathological analysis revealed severe damage in the renal tissue of DOX treated animals. However, animals pretreated with LycT were observed to have reduced damage. Thus, from present results it may be inferred that lycopene may be beneficial in mitigating DOX induced nephrotoxicity in mice.

Avaliação da expressão imunoistoquímica de proteínas da via de sinalização mediada por TGFβ como preditores de resposta à quimioterapia pré-operatória em adultos portadores de sarcoma de partes moles de alto grau em extremidades / Protein expression evaluation of protein of genes belonging to the TGFβ pathway as predictors of response to preoperative chemotherapy with doxorubicin and ifosfamide in adult patients with high grade soft tissue sarcomas located in extremities

Introdução: Sarcomas de partes moles (SPM) constituem um grupo de neoplasias raras de comportamentos distintos. O tratamento para os tumores de alto grau, não passiveis de ressecção adequada, é feito por cirurgia, radioterapia (RT) e quimioterapia (QT). Apesar disso, 50% dos pacientes com tumores localizados ao diagnóstico morrem da doença metastática. A QT pré-operatória para o tratamento de tumores localizados, apesar de não ser considerada como padrão, é uma opção promissora. A escassez de preditores biológicos de resposta, e achados de que a superexpressão de genes pertencentes à via mediada por TGFβ estaria relacionada à resistência à QT nos levaram à tentativa de estabelecer a relação entre a expressão de FST, SMAD4, TGFβ e Id com resposta patológica. Objetivos: Avaliar por imunoistoquímica (IQ) a expressão das proteínas produzidas a partir dos genes TGFB, FST, Id1 e SMAD4 da via mediada por TGFβ, correlacionando com a resposta patológica; expandir os resultados clínicos do esquema de QT pré-operatória com doxorrubicina e ifosfamida em vigência no Hospital A.C. Camargo; determinar as taxas de toxicidade e avaliar um método de análise patológica que quantifique a percentagem de células tumorais viáveis em peça operatória. Pacientes e Métodos: 42 pacientes com SPM de alto grau localizados em extremidades, tratados com doxorrubicina e ifosfamida pré-operatória, foram observados de forma prospectiva, desde janeiro de 2005 a agosto de 2012. Amostras das biópsias e das peças operatórias foram obtidas e submetidas à pesquisa da expressão das proteínas já referidas por IQ. Resultados: A expressão das proteínas estudadas não teve correlação estatisticamente significativa com a resposta patológica...

Backgraund: Soft Tissue Sarcomas (STS) are rare neoplasms with many histological subtypes, behaviors and response to different treatments. The treatment of these tumors involves surgery, radiation and chemotherapy. Despite that 50% of patients with localized tumors will develop metastatic disease. Preoperative chemotherapy (CT) although not standard is considered a promising therapeutic option. The lack of biological predictors of response, led us to study the relationship between the expression of FST, SMAD4, TGFβ and Id (TGFβ superfamily genes) in patients submitted to preoperative CT. Objectives: To evaluate the protein expression. Produced by genes belonging to the TGFβ pathway by IH and correlate it with pathologic response; expand the preliminary results of a previous phase II trial testing a schedule of preoperative CT with doxorubicin and ifosfamide in Hospital A.C. Camargo; determine the rate of toxicity and evaluate a method of assessing pathological analysis that quantifies the percentage of viable tumor cells in surgical specimens. Patients and Methods: 42 patients with high grade STS located in extremities treated with preoperative doxorubicin and ifosfamide CT were observed prospectively, on a non controlled fashion since January 2005 to august 2012. Biopsies and surgical specimens were obtained to enable the analysis of TGFβ, FST, SMAD4 and Id protein expressional by immunohistochemistry (IH). Results: The expression of the proteins studied had no significant association with pathological response. The objective response rates of the primary tumor were 17.5% for clinical response and 15% for pathologic complete response. Only 7.5% patients had a limb amputated. The rate of surgical contraindication was 4.7%. Grade 3-4 toxicity occurred in 45.2% of cases. Conclusion: The method of pathological response analysis was considered easily applicable. TGFβ-mediated pathway proteins studied did not correlate with pathological response...

Avaliação das alterações cardiotóxicas decorrentes do uso da doxorrubicina: estudo experimental em ratos / Clinical evaluation of the doxorubicin-induced cardiotoxicity: experimental study in rats

A doxorrubicina é um dos quimioterápicos mais utilizados no tratamento de tumores sólidos e hematopoiéticos, embora possa causar reações adversas, especialmente cardiomiopatia secundßria. Apesar do potencial cardiotóxico, a doxorrubicina ainda é amplamente utilizada devido a sua alta eficßcia e baixo custo. esse trabalho objetiva-se estudar a sintomatologia associada ao uso da doxorrubicina em ratos, para elucidar seus efeitos cardiotóxicos. Dez ratos Wistar machos foram distribuidos em dois grupos: tratado, o qual recebeu 5mg/kg de doxorrubicina em 1,0mL de salina, via intraperitoneal a cada sete dias, durante quatro se- manas; e controle, o qual recebeu apenas 1,0 mL de salina nas mesmas condições descritas. Realizou-se eletrocardiograma antes dos tratamentos e após quatro semanas, juntamente com ecocardiograma. Os animais do grupo tratado apresentaram apatia, emagrecimento, desidratação e fezes diarreicas com muco, indicando disfunção metabólica decorrente da toxicidade do quimioterßpico. Em dois animais, o quadro clínico evoluiu para óbito, 19 dias após início do tratamento. No eletrocardiograma detectou-se aumento na amplitude das ondas P e R, sugerindo sobrecarga atrial e ventricular esquerda, respectivamente. A onda T apresentou amplitude superior à onda R, provavelmente devido a alterações eletrolíticas secundßrias ao quadro de desidratação e diarreia. Arritmias atriais e ventriculares, contudo, não foram detectadas. Foi diagnosticada disfunção ventricular nos animais que receberam doxorrubicina, quando avaliados por ecocardiografia de deformação miocßrdica (velocidade e deslocamento radiais do ventrículo esquerdo). Conclui-se que a doxorrubicina provoca cardiotoxicidade dose-dependente com redução progressiva da função ventricular esquerda, a qual pode ser diagnosticada precocemente com a ecocardiografia strain...

Doxorubicin is one of lhe most common drugs used in lhe treatment of solid and emopoietic tumors; however it causes a dose-dependet adverse effects, mainly cardiomyopathy. Despite the obvious cardiac toxicity potential, doxorubicin is still widely used due t0 its high efficiency and low cost. Therefore, this research aims to study the sytmptoms associated with the use of doxorubicin in rats, in order to elucidate its cardiac toxicity. Ten male Wistar rats were distributed into two groups: treated, which received 5mg/kg of doxorubicin in 1.0 mL saline intraperitoneal weekly, for four weeks, and control, which received only 1.0 mL of saline under lhe same conditions described. Electrocardiography was performed before treatment and atter four weeks when echocardiography was done as well. The treated group showed apathy, weight loss, dehydration and diarrheal stools with mucus, indicating metabolic dystunction due to the toxicity of chemotherapy. Two animals died, 19 days after lhe beginning of the experiment The electrocardiogram detected an increase in the amplitude of P. R and S waves, suggesting atrial and ventricular overload, respectively. The greater amplitude of the T-wave when compared to the R wave occurred probably due to electrolyte alterations caused by dehydration and diarrhea. Nevertheless, atrial and ventricular ar- rhythmias were not detected. Ventricular dysfunction was diagnosed in animais that received doxorubicin when evaluated by strain echocardiography (left ventricular radial velocity and displacement). It was concluded that doxorubicin causes a dose-dependent cardiotoxicity, with a progressive left ventricular dysfunction which may be early detected using the strain echocardiography...

Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals

We analyzed the in vitro effects of the anti-tumoral drugs doxorubicin, cytosine arabinoside and hydroxyurea on the G2-prophase checkpoint in lymphocytes from healthy individuals. At biologically equivalent concentrations, the induced DNA damage activated the corresponding checkpoint. Thus: i) there was a concentration-dependent delay of G2 time and an increase of both the total DNA lesions produced and repaired before metaphase and; ii) G2-checkpoint adaptation took place as chromosome aberrations (CAs) started to appear in the metaphase, indicating the presence of unrepaired double-strand breaks (DSBs) in the previous G2. The checkpoint ATM/ATR kinases are involved in DSB repair, since the recorded frequency of CAs increased when both kinases were caffeine-abrogated. In genotoxic-treated cells about three-fold higher repair activity was observed in relation to the endogenous background level of DNA lesions. The maximum rate of DNA repaired was 3.4 CAs/100 metaphases/hour, this rise being accompanied by a modest 1.3 fold lengthening of late G2 prophase timing. Because of mitotic chromosome condensation, no DSBs repair can take place until the G1 phase of the next cell cycle, when it occurs by DNA non-homologous end joining (NHEJ). Chromosomal rearrangements formed as a consequence of these error-prone DSB repairs ensure the development of genome instability through the DNA-fusion-bridge cycle. Hence, adaptation of the G2 checkpoint supports the appearance of secondary neoplasia in patients pretreated with genotoxic drugs.

Anatomopathological study of cardiomyopathy induced by doxorubicin in rats / Estudo anatomopatológico da miocardiopatia induzida pela doxorrubicina em ratos

Purpose: The development of an experimental model of myocardiopathy induced by Doxorubicin in rats. Methods: 16 wistar male rats were randomized in two groups: Group I (placebo) and Group II (Doxorubicin - 5mg/kg). After six months, the animals were subjected to cardiotomy and their hearts were weighted and submitted to transversal cuts, from which fragments for a macro and micro study were obtained. These fragments were studied considering their external and internal diameters and the thickness of the left ventricle (LV). The histological pieces were analyzed for the presence of fibrosis, cytoplasmic vacuolization, necrosis and size of nucleus variation. Data obtained was submitted to statistical analysis with Student's t test. Results: The hearts of the animals in Group II increased 41 percent in relation to their weight; 33 percent in the internal diameter and 14 percent in the external diameter of the LV cavity; and 24 percent in the thickness of the wall. Fibrosis of the myocardial tissue was observed in 75 percent of the animals of Group II; all the animals presented miocyte cytoplasmatic vacuolization; myocardial necrosis was present in 75 percent of the animals; and 87/ percent presented variation in the size of myocite nuclei. The presence of polymorphonuclear cells was also observed. Conclusion: Doxorubicin was effective in the promotion of macro and microscopic alterations in the cardiac tissue of rats, possibly constituting a model for the experimental study of myocardiopathy.

Objetivo: Desenvolver um modelo experimental de miocardiopatia induzida por doxorrubicina em ratos. Métodos: 16 ratos Wistar machos foram randomizados em 2 grupos: Grupo I (placebo) e Grupo II (doxorrubicina 5mg/kg). Após 6 meses, os animais foram submetidos a cardiotomia e seus corações foram pesados e submetidos a cortes transversais. Estes fragmentos foram estudados considerando seus diâmetros externos e internos e a espessura do ventrículo esquerdo. As peças histológicas foram analisadas quanto à presença de fibrose, vacuolização citoplasmática, necrose e variação do tamanho do núcleo. Os resultados foram submetidos a análise estatística pelo teste t de Student. Resultados: Os corações dos animais do grupo II aumentaram 41 por cento em relação ao peso; 33 por cento no diâmetro interno e 14 por cento no diâmetro externo; e 24 por cento na espessura da parede do VE. Fibrose do tecido miocárdico foi observada em 75 por cento dos animais do grupo II; todos os animais apresentaram vacuolização citoplasmática dos miócitos; Houve necrose miocárdica em 75 por cento dos animais e 87 por cento apresentaram variação no tamanho do núcleo. A presença de células polimorfonucleares também foi observada. Conclusão: A doxorrubicina foi efetiva na promoção de alterações macro e microscópicas no tecido cardíaco de ratos, possivelmente constituindo-se num modelo experimental para estudo da miocardiopatia.

Cardioprotective effect of simvastatin on doxorubicin-induced oxidative cardiotoxicity in rats

The usefulness of doxorubicin [DOX], a highly effective antitumor drug, is limited by the risk of developing cardiomyopathy. Subcellular changes leading to this toxicity are suggested to be mediated through a drug-induced increase in free radicals and lipid peroxidation. The present study was undertaken to investigate the possible protection that simvastatin [SIM], a lipid-lowering drug, can offer against DOX induced cardiotoxicity. DOX was administered to male Swiss albino rats in 6 equal interaperitoneal injections over a period of 2 weeks [cumulative dose, 15 mg/kg]. Protection from doxorubicin-oxidative injury was investigated by administration of SIM [cumulative dose, 60 mg /kg] in 12 equal oral doses over a period of 4 weeks [2 weeks before and 2 weeks concurrent with doxorubicin]. At the end of treatment, ECG was performed; myocardial antioxidants and lipid peroxidation were assayed. In addition, body weight changes during the experiment, mortality%, and histopathological examination of the heart tissue were performed. DOX treatment increased peritoneal fluid, myocardial oxidative damage and decreased survival. Myocardial antioxidants including reduced glutathione [GSH], glutathione-S-transferase [GST], and DT-diaphorase activities were reduced, while lipid peroxidation was increased. Administration of SIM before and concurrent with DOX significantly reduced the oxidative myocardial changes-induced by DOX treatment. It also decreased mortality, and eliminated ascites. Histopathological observations were in correlation with the biochemical parameters. This indicates that SIM provide protection from DOX-induced cardiac injury in terms of oxidative stress