ABSTRACT
Introduction: DMBA is a chemical carcinogen that induces carcinomas within a few weeks of its application. We developed an experimental model of carcinogenesis induced by DMBA dissolved in 0,5% paraffin oil (DMBA-PO), verifying the inhibitory effect of the carcinogenicity of phenyl isothiocyanate (PhITC), phenethyl (PhnITC) and benzyl isothiocyanate (BITC). Material and Methods: For this, 88 hamsters were distributed into three groups: one exposed to DMBA-PO (Group 1, n=12), three subgroups (n=12) exposed to PhITC, PhnITC, BITC and DMBA-PO (Group 2, n=36) and four control subgroups (n=10) that were not exposed to the carcinogen in which PO (paraffin oil) and isothiocyanates were applied (Group 3, n=40). Results: The experiment had a duration of 20 weeks, at the end of which the inhibitory effect was established by comparing the lesions developed in the groups that received isothiocyanates with the group that was only treated with DMBA-PO. The carcinogenic effect of DMBA-PO is 100% (35 carcinomas) and the inhibitory effect was 0, whereas in the presence of isothiocyanates the carcinogenic effect decreases, with an inhibitory effect of 86% for BITC (5 carcinomas) and 74% for PhITC (9 carcinomas). Conclusion: The inhibitory effect for PhnITC is 80% in relation to invasive OSCC (1 carcinoma).
Introducción: El DMBA es un carcinógeno químico que induce carcinomas a las pocas semanas de su aplicación. Desarrollamos un modelo experimental de carcinogénesis inducida por DMBA disuelto en aceite de parafina al 0,5% (DMBA-Ap) comprobando el efecto inhibidor de la carcinogénesis de los isotiocianatos fenil (PhITC), fenetil (PhnITC) y bencil isotiocianato (BITC). Material y Métodos: Para ello, se distribuyeron 88 hámsteres en 3 grupos: uno expuesto al DMBA-Ap (Grupo 1, n=12), tres subgrupos (n=12) expuestos a PhITC, PhnITC, BITC y DMBA-Ap (Grupo 2, n=36) y cuatro subgrupos controles (n=10), no expuestos al carcinógeno en el que se aplicaron Ap e isotiocianatos (Grupo 3, n=40). Resultados:El experimento tuvo una duración de 20 semanas, al final de la cual se establece de forma comparativa el efecto inhibidor comparando las lesiones desarrolladas en los grupos que recibieron isotiocianatos con respecto al grupo tratado sólo con DMBA-Ap. El efecto carcinógeno del DMBA-Ap es del 100% (35 carcinomas) y el efecto inhibidor 0, mientras que en presencia de isotiocianatos el efecto carcinógeno disminuye, con un efecto inhibidor del 86% para BITC (5 carcinomas) y del 74% para el PhITC (9 carcinomas). Conclusión:El efecto inhibidor del PhnITC es del 80% en relación con el COCE invasivo (1 carcinoma).
Subject(s)
Animals , Male , Anticarcinogenic Agents/therapeutic use , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Carcinogens , Isothiocyanates , Models, Animal , Carcinogenesis , Squamous Cell Carcinoma of Head and NeckABSTRACT
ABSTRACT Objective: to evaluate the influence of Ki-67 and P16INK4a proteins immunohistochemical expressions on the clinical and morphological parameters of perioral squamous cell carcinoma induced with 9,10-dimethyl-1,2-benzanthracene (DMBA) in mice. Methods: we topically induced the lesions in the oral commissure of ten Swiss mice for 20 weeks, determining the time to tumors onset and the average tumor volume up to 26 weeks. In histopathological analysis, the variables studied were histological malignancy grade and the immunohistochemical expression of Ki-67 and P16INK4a proteins. The correlation between variables was determined by application of the Spearman correlation test. Results: the mean time to onset of perioral lesions was 21.1 ± 2.13 weeks; mean tumor volume was 555.91 ± 205.52 mm3. Of the induced tumors, 80% were classified as low score and 20% high score. There was diffuse positivity for Ki-67 in 100% of lesions - Proliferation Index (PI) of 50.1 ± 18.0. There was a strong direct correlation between Ki-67 immunoreactivity and tumor volume (R = 0.702) and a low correlation with the malignancy score (R = 0.486). The P16INK4a protein expression was heterogeneous, showing a weak correlation with tumor volume (R = 0.334). There was no correlation between the immunohistochemical expression of the two proteins studied. Conclusion: in an experimental model of DMBA-induced perioral carcinogenesis, tumor progression was associated with the tumor proliferative fraction (Ki-67 positive cells) and with tumor histological grading, but not with P16INK4a expression.
RESUMO Objetivo: avaliar a influência da expressão imuno-histoquímica das proteínas Ki-67 e p16INK4a sobre parâmetros clínico-morfológicos em carcinomas espinocelulares periorais quimicamente induzidos com 9,10-dimetil-1,2-benzantraceno (DMBA) em modelo murino. Métodos: as lesões foram induzidas topicamente na comissura labial de dez camundongos Swiss durante 20 semanas, sendo determinado o momento de surgimento dos tumores e volume tumoral médio até 26 semanas. Na análise histopatológica, as variáveis estudadas foram gradação histológica de malignidade tumoral e expressão imuno-histoquímica das proteínas Ki-67 e p16INK4a. A correlação entre as variáveis estudadas foi determinada pela aplicação do teste de correlação de Spearman. Resultados: o tempo médio de surgimento das lesões periorais foi 21,1±2,13 semanas. Volume tumoral médio foi de 555,91±205,52mm3. Dos tumores produzidos, 80% foram classificados como de baixo escore e 20%, alto escore. Evidenciou-se positividade difusa para Ki-67 em 100% das lesões - índice de marcação (PI) de 50,1±18,0. Verificou-se correlação direta forte entre a imunoexpressão do Ki-67 e o volume tumoral (R=0,702) e fraca correlação com o escore de malignidade (R=0,486). A expressão da proteína p16INK4a foi heterogênea, mostrando fraca correlação com o volume tumoral (R=0,334). Não houve correlação entre a expressão imuno-histoquímica das duas proteínas estudadas. Conclusão: Em modelo experimental de carcinogênese perioral DMBA-induzida, a progressão tumoral está associada à fração proliferativa do tumor (células ki-67 positivas) e com a gradação histológica tumoral, porém não com a expressão da p16INK4a.
Subject(s)
Animals , Mouth Neoplasms/metabolism , Carcinoma, Squamous Cell/metabolism , Ki-67 Antigen/biosynthesis , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Neoplasms, Experimental/metabolism , Mouth Neoplasms/chemically induced , Carcinoma, Squamous Cell/chemically induced , Mice , Neoplasms, Experimental/chemically inducedABSTRACT
O câncer de mama é a neoplasia maligna mais prevalente e a principal causa de óbito entre mulheres, no mundo. A despeito de avanços substanciais no entendimento da biologia da doença, nos métodos de detecção precoce, e em sua farmacoterapia, a sobrevida geral não se modificou significantemente nas últimas décadas. Portanto, pode se dizer que um dos deveres primordiais das Universidades Públicas engajadas com pesquisa básica e aplicadas consiste em contribuir para o desenvolvimento de novas estratégias de tratamento sistêmico desta neoplasia. Nesse contexto, um dos alvos estratégicos mais promissores no desenvolvimento de novos fármacos antineoplásicos é representado pela célula-tronco neoplásica (CTN). As CTNs têm sido associadas em inúmeros estudos à capacidade de algumas neoplasias malignas de resistir às principais modalidades terapêuticas antineoplásicas, especialmente à: radio-, quimio-, hormônio- e imunoterapias. Em resumo, na atualidade, a detecção de CTNs constitui uma ferramenta clínica bastante promissora enquanto alvo terapêutico, fator prognóstico e preditivo de resposta terapêutica. O objetivo deste trabalho foi descrever e discutir as potencialidades e limitações do modelo de carcinogênese mamária pelo DMBA, após reclassificação das neoplasias mamárias segundo os critérios diagnósticos da OMS (2003, 2012), subtipagem molecular e quantificação de imunomarcadores prognósticos, preditivos e de CTN. Após a aplicação do protocolo experimental de indução química pelo DMBA e a eutanásia dos animais controle e experimental, suas linhas mamárias (contendo ou não tumores) foram ressecadas e avaliadas quanto à morfologia e a imunoexpressão para marcadores de CTNs. Após 13 semanas, 100% dos animais desenvolveram neoplasias macroscópicas e histologicamente compatíveis com os critérios de avaliação indicados pela OMS.
Breast cancer is the most common malignancy and the leading cause of death from cancer among females worldwide. Despite all the research and all the progress, methods of early detection, and its pharmacotherapy, overall survival has not changed significantly in recent decades. Therefore, the Public University has been engaged in basic and applied research is too contributed to the development of new strategies for systemic treatment of this malignancy. In this context, one of the most promising strategic targets in the development of the anticancer drugs is represented by neoplastic stem cell (NSC). Neoplastic stem cell has been linked in various studies to the capacity of some malignancies to resist major antineoplastic therapeutic modalities, especially: radio-, chemo-, hormone- and immunotherapies. In summary, the detection of NSCs is a clinical tool very promising while therapeutic target and prognostic factor predictive of therapeutic response. The aim of this study was to describe and discuss the strengths and limitations of the model of mammary carcinogenesis by DMBA, after reclassification of breast cancer according to the diagnostic criteria of the WHO (2003, 2012), and quantification of molecular subtyping prognostic immunomarkers, predictive and NSC. After application of the experimental protocol of chemical induction by DMBA and euthanasia of experimental and control animals, the mammary lines (with or without tumors) were resected and evaluated the morphology and immunostaining for markers of NSCs. After 13 weeks, 100% of the animals developed macroscopic neoplasms and histologically consistent with the evaluation criteria of evaluation indicated by WHO. Tumors were classified as ductal carcinoma, papillary carcinoma, lobular carcinoma, myoepithelial carcinoma and phyllodes tumor, being the most common type, the ductal. Few immunohistochemical markers correlated with variable behavior biological.
Subject(s)
Animals , Rats , Breast Neoplasms , Histology, Comparative/methods , Neoplastic Stem Cells , Neoplasms/diagnosis , Rats, Sprague-DawleyABSTRACT
Studies have demonstrated that flavonoid compounds of green propolis have antitumoral activity. STUDY DESIGN: Experimental study. AIMS: To evaluate the effect of a hydroalcoholic extract of green propolis (EPV) on chemically induced epithelial dysplasias in rat tongues. METHODS AND MATERIALS: DMBA was brushed on the lingual dorsum of rats 3x/week on alternate days - 100 (PROP1), 200 (PROP2) and 300 mg/kg (PROP3) EPV was administered orally for 20 weeks. EPV or DMBA were replaced by their vehicles and applied as positive (TUM1 and TUM2) and negative controls (CTR1 and CTR2), respectively. The lingual epithelium was histologically analyzed and graded according a binary system and the WHO classification; the data were compared using ANOVA (*p<0.05). RESULTS: The EPV yield was 41 percent and the flavonoid yield was 0.95±0.44 percent. According to the Binary System, TUM1, TUM2 and PROP1 were considered high risk lesions, with significantly higher morphological alteration rates compared to the other groups (p<0.05), which were considered low risk lesions. Based on the WHO classification, moderate dysplasia was TUM1 and TUM2, mild dysplasia was PROP1, PROP2 and PROP3, and non-dysplastic epithelium was CTR1 and CTR2. CONCLUSION: EPV seems to play an important protective role against chemically-induced lingual carcinogenesis in rats.
Estudos têm demonstrado que componentes hidrossolúveis da própolis verde, flavonóides, apresentam atividade antitumoral. FORMA DE ESTUDO: Estudo experimental. OBJETIVO: Avaliar o efeito do extrato hidroalcoólico de própolis verde (EPV) sobre displasias epiteliais linguais quimicamente induzidas em ratos. MATERIAIS E MÉTODOS: Neste estudo, foi pincelado DMBA (9,10-dimetil-1,2- benzatraceno) no dorso lingual de ratos 3x/semana, em dias alternados, administrado 100 (PROP1), 200 (PROP2) e 300 mg/kg (PROP3) de EPV (v.o.), durante 20 semanas. A substituição do EPV ou DMBA pelos seus veículos foi usada nos controles positivos (TUM1 e TUM2), negativos (CTR1 e CTR2), respectivamente. O epitélio lingual foi analisado histologicamente, graduado pelo Sistema Binário e classificação OMS, e os dados comparados por análise de variância (ANOVA) (p<0,05). RESULTADOS: O rendimento do EPV foi 41,43 por cento e o teor de flavonóides 0,95±0,44 por cento. Segundo o Sistema Binário, TUM1, TUM2 e PROP1 foram considerados lesões de alto risco, apresentando índices de alterações morfológicas significativamente mais elevados (p<0,05), e os demais de baixo risco. Segundo a classificação OMS, observou-se displasia moderada em TUM e TUM2, leve em PROP1, PROP2 e PROP3, e ausente em CTR1 e CTR2. Conclusão: Sugere-se que o EPV possa desempenhar um papel protetor importante durante a carcinogênese lingual quimicamente induzida em ratos. CONCLUSÃO: Sugere-se que o EPV possa desempenhar um papel protetor importante durante a carcinogênese lingual quimicamente induzida em ratos.
Subject(s)
Animals , Male , Rats , Epithelial Cells/drug effects , Propolis/therapeutic use , Tongue Neoplasms/prevention & control , Carcinogens , Cell Transformation, Neoplastic , Epithelial Cells/pathology , Precancerous Conditions/chemically induced , Precancerous Conditions/pathology , Precancerous Conditions/prevention & control , Rats, Wistar , Severity of Illness Index , Tongue Neoplasms/chemically induced , Tongue Neoplasms/pathologyABSTRACT
Objetivo: Testar um modelo experimental de indução de carcinogênese em raras Sprague-Dawley. Métodos: Foram estudadas 30 ratas fêmeas virgens Sprague-Dawley, induzidas ao carcinogênese mamário. Com 50 dias de vida, foi injectado 7,12-dimerilbenz(a)antrace no ventre por gavage. Com 12 semanas, as glândulas mamárias foram examinadas, assim como os tecidos cerebrais, pulmonares, ossos do fêmur e fígado. Resultados: Doze semanas após a injeção de DMBA, 85% das ratas apresentaram pelo menos um tumor mamário visível. Conclusão: O modelo experimental de carcinoma mamário induzido por DMBA mostrou-se efetivo e de fácil reprodução.
Objective: To test an experimental model of chemical mammary carcinogenesis induction in Sprague-Dawley rats. Methods: Thirty virgin Sprague-Dawley female rats, aged 50 days, received 20 mg of 7,12-dimethyLbenz(a)anthracene (DMBA) intragastrically by gavage. At 12 week their mammary glands were examined. Brain, Liver, bone and Lung tissue were also analyzed. Results: Twelve weeks after DMBA injection, 85% rats presented at Least one breast tumor. Conclusion: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.