RESUMO
OBJECTIVE: The aim of the present study was to evaluate the local and regional therapeutic efficacy and abscopal effect of BNCT mediated by boronophenyl-alanine, combined with Bacillus Calmette-Guerin (BCG) as an immunotherapy agent in this model. METHODS: The local effect of treatment was evaluated in terms of tumor response in the irradiated tumor-bearing right hind flank. Metastatic spread to tumor-draining lymph nodes was analyzed as an indicator of regional effect. The abscopal effect of treatment was assessed as tumor growth inhibition in the contralateral (non-irradiated) left hind flank inoculated with tumor cells 2 weeks post-irradiation. The experimental groups BNCT, BNCT + BCG, BCG, Beam only (BO), BO +BCG, SHAM (tumor-bearing, no treatment, same manipulation) were studied. RESULTS: BNCT and BNCT + BCG induced a highly significant local anti-tumor response, whereas BCG alone induced a weak local effect. BCG and BNCT + BCG induced a significant abscopal effect in the contralateral non-irradiated leg. The BNCT + BCG group showed significantly less metastatic spread to tumor-draining lymph nodes vs SHAM and vs BO. CONCLUSION: This study suggests that BNCT + BCG-immunotherapy would induce local, regional and abscopal effects in tumor-bearing animals. BNCT would be the main effector of the local anti-tumor effect whereas BCG would be the main effector of the abscopal effect. ADVANCES IN KNOWLEDGE: Although the local effect of BNCT has been widely evidenced, this is the first study to show the local, regional and abscopal effects of BNCT combined with immunotherapy, contributing to comprehensive cancer treatment with combined therapies.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias do Colo/terapia , Imunoterapia/métodos , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/radioterapia , Terapia Combinada/métodos , Modelos Animais de Doenças , Feminino , Masculino , Ratos , Resultado do TratamentoRESUMO
The patient's hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple-negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed an increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens but increased activated CD8+ cells and the IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. A better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.
Assuntos
Neoplasias da Mama , Hipertireoidismo , Hipotireoidismo , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-10/uso terapêutico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Microambiente TumoralRESUMO
The photothermal effect is undergoing great interest due to advances in new photosensitizing materials and better-suited light sources, but studies are frequently hampered by the need to employ exogenous photothermal agents and expensive irradiation devices. Here we present a simple strategy based on direct NIR irradiation of the melanin pigment with a commercial 808-nm laser pointer. Proof-of-concept studies showed efficient photothermal effects on melanin in vitro and in vivo. After NIR irradiation, BALB/c mice bearing B16-F10 melanotic melanoma tumors revealed severe histopathological damage and massive necrosis in melanin-containing tumor tissue, while surrounding healthy tissues showed no damage. Therefore, the feasibility of this approach may allow implementing direct procedures for photothermal therapy of pigmented tumors.
RESUMO
Boron neutron capture therapy (BNCT) is a promising cancer binary therapy modality that utilizes the nuclear capture reaction of thermal neutrons by boron-10 resulting in a localized release of high- and low-linear energy transfer (LET) radiation. Electrochemotherapy (ECT) is based on electroporation (EP) that induces opening of pores in cell membranes, allowing the entry of compounds. Because EP is applied locally to a tumor, the compound is incorporated preferentially by tumor cells. Based on the knowledge that the therapeutic success of BNCT depends centrally on the boron content in tumor and normal tissues and that EP has proven to be an excellent facilitator of tumor biodistribution of an anti-tumor agent, the aim of this study was to evaluate if EP can optimize the delivery of boronated compounds. We performed biodistribution studies and qualitative microdistribution analyses of boron employing the boron compound sodium decahydrodecaborate (GB-10) + EP in the hamster cheek pouch oral cancer model. Syrian hamsters with chemically induced exophytic squamous cell carcinomas were used. A typical EP treatment was applied to each tumor, varying the moment of application with respect to the administration of GB-10 (early or late). The results of this study showed a significant increase in the absolute and relative tumor boron concentration and optimization of the qualitative microdistribution of boron by the use of early EP + GB-10 versus GB-10 without EP. This strategy could be a tool to improve the therapeutic efficacy of BNCT/GB-10 in vivo.
Assuntos
Compostos de Boro/metabolismo , Terapia por Captura de Nêutron de Boro/métodos , Boro/metabolismo , Isótopos/metabolismo , Animais , Bochecha , Cricetinae , Modelos Animais de Doenças , Mesocricetus , Neoplasias Bucais , Distribuição TecidualRESUMO
Galectin-8 (Gal-8), a 'tandem-repeat'-type galectin, has been described as a modulator of cellular functions including adhesion, spreading, growth arrest, apoptosis, pathogen recognition, autophagy, and immunomodulation. We have previously shown that activated leukocyte cell adhesion molecule (ALCAM), also known as CD166, serves as a receptor for endogenous Gal-8. ALCAM is a member of the immunoglobulin superfamily involved in cell-cell adhesion through homophilic (ALCAM-ALCAM) and heterophilic (i.e. ALCAM-CD6) interactions in different tissues. Here we investigated the physiologic relevance of ALCAM-Gal-8 association and glycosylation-dependent mechanisms governing these interactions. We found that silencing of ALCAM in MDA-MB-231 triple negative breast cancer cells decreases cell adhesion and migration onto Gal-8-coated surfaces in a glycan-dependent fashion. Remarkably, either Gal-8 or ALCAM silencing also disrupted cell-cell adhesion, and led to reduced tumor growth in a murine model of triple negative breast cancer. Moreover, structural characterization of endogenous ALCAM N-glycosylation showed abundant permissive structures for Gal-8 binding. Importantly, we also found that cell sialylation controls Gal-8-mediated cell adhesion. Altogether, these findings demonstrate a central role of either ALCAM or Gal-8 (or both) in controlling triple negative breast cancer.
Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Fetais/metabolismo , Galectinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antígenos CD/genética , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Linhagem Celular Tumoral , Feminino , Proteínas Fetais/genética , Galectinas/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteínas de Neoplasias/genética , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
PURPOSE: Boron neutron capture therapy (BNCT) combines selective accumulation of 10B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies. MATERIALS AND METHODS: We evaluated tumor control and toxicity in lung 2 weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA + Sodium decahydrodecaborate-BNCT ((BPA + GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood. RESULTS AND CONCLUSIONS: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48 days) versus Sham (33 days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity. Highlights Boron Neutron Capture Therapy suppresses growth of experimental lung metastases No BNCT-induced short/medium-term toxicity in lung is associated with tumor control Boron Neutron Capture Therapy increased post-treatment survival time by 45.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Pulmonares/radioterapia , Pesquisa Translacional Biomédica , Animais , Terapia por Captura de Nêutron de Boro/efeitos adversos , Linhagem Celular Tumoral , Neoplasias do Colo/secundário , Relação Dose-Resposta à Radiação , Neoplasias Pulmonares/patologia , Radiometria , Ratos , Análise de SobrevidaRESUMO
The aim of the present study was to evaluate, for the first time, the abscopal effect of boron neutron capture therapy (BNCT). Twenty-six BDIX rats were inoculated subcutaneously with 1 × 106 DHD/K12/TRb syngeneic colon cancer cells in the right hind flank. Three weeks post-inoculation, the right leg of 12 rats bearing the tumor nodule was treated with BPA-BNCT (BPA-Boronophenylalanine) at the RA-3 nuclear reactor located in Buenos Aires, Argentina, at an absorbed dose of 7.5 Gy to skin as the dose-limiting tissue. The remaining group of 14 tumor-bearing rats were left untreated and used as control. Two weeks post-BNCT, 1 × 106 DHD/K12/TRb cells were injected subcutaneously in the contralateral left hind flank of each of the 26 BDIX rats. Tumor volume in both legs was measured weekly for 7 weeks to determine response to BNCT in the right leg and to assess a potential influence of BNCT in the right leg on tumor development in the left leg. Within the BNCT group, a statistically significant reduction was observed in contralateral left tumor volume in animals whose right leg tumor responded to BNCT (post-treatment/pre-treatment tumor volume <1) versus animals who failed to respond (post/pre ≥1), i.e., 13 ± 15 vs 271 ± 128 mm3. In addition, a statistically significant reduction in contralateral left leg tumor volume was observed in BNCT-responsive animals (post/pre <1) vs untreated animals, i.e., 13 ± 15 vs 254 ± 251 mm3. The present study performed in a simple animal model provides proof of principle that the positive response of a tumor to BNCT is capable of inducing an abscopal effect.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias do Colo/radioterapia , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Imunoterapia , Masculino , Metástase Neoplásica , RatosRESUMO
There is clinical and experimental evidence suggesting that antiprogestins might be used for the treatment of selected breast cancer patients. Our aim was to evaluate the effect of albumin-bound paclitaxel (Nab-paclitaxel) and pegylated doxorubicin liposomes (PEG-LD) in combination with mifepristone (MFP) in experimental breast cancer models expressing different ratios of progesterone receptor (PR) isoforms A and B. We used two antiprogestin-responsive (PRA>PRB) and two resistant (PRAAssuntos
Antineoplásicos/administração & dosagem
, Neoplasias da Mama/metabolismo
, Mifepristona/administração & dosagem
, Receptores de Progesterona/metabolismo
, Albuminas/administração & dosagem
, Animais
, Doxorrubicina/administração & dosagem
, Feminino
, Imunofluorescência
, Humanos
, Imuno-Histoquímica
, Lipossomos
, Camundongos
, Camundongos Endogâmicos BALB C
, Camundongos Nus
, Nanopartículas
, Paclitaxel/administração & dosagem
, Isoformas de Proteínas
, Ensaios Antitumorais Modelo de Xenoenxerto
RESUMO
Bladder cancer is the second cause of death for urological tumors in man. When the tumor is nonmuscle invasive, transurethral resection is curative. On the other hand, radical cystectomy is the treatment chosen for patients with invasive tumors, but still under treatment, these patients have high risk of dying, by the development of metastatic disease within 5 years. It is therefore important to identify a new therapeutic target to avoid tumor recurrences and tumor progression. Nitric oxide (NO) is an important biological messenger known to influence several types of cancers. In bladder cancer, production of NO and expression and activity of inducible NO synthase was associated to recurrence and progression. The objective of this work was to analyze if inhibition of nitric oxide production could be considered a therapeutic target for bladder tumors expressing iNOS. Using a bladder cancer murine model with different invasiveness grade we have demonstrated that NO inhibition was able to inhibit growth of bladder tumors expressing iNOS. Furthermore, invasive properties of MB49-I orthotopic growth was inhibited using NO inhibitors. This paper also shows that levels of NO in urine can be correlated with tumor size. In conclusion, inhibition of NO could be considered as a therapeutic target that prevents tumor growth and progression. Also, urine NO levels may be useful for measuring tumor growth.
Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/química , Neoplasias da Bexiga Urinária/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Meios de Cultivo Condicionados/química , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Transplante de NeoplasiasRESUMO
Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFß) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFß signals through the complex of TGFß type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFß1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TßRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFß1 anti-mitogenic effects and TGFß1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFß1 treatment was observed at the metastatic site. In our model, TGFß1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFß1-mediated metastasis stimulation. Several of these TGFß responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TßRI in human lung tumors is associated with poor patient's overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.
Assuntos
Adenocarcinoma/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Adesão Celular , Ciclo Celular , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Imunofluorescência , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
OBJECTIVE: This study aimed to investigate whether the overexpression of protein kinase C ß1 (PKCß1) is able to modulate the malignant phenotype displayed by the human ductal pancreatic carcinoma cell line PANC1. METHODS: PKCß1 overexpression was achieved using a stable transfection approach. PANC1-PKCß1 and control cells were analyzed both in vitro and in vivo. RESULTS: PANC1-PKCß1 cells displayed a lower growth capacity associated with the down-regulation of the MEK/ERK pathway and cyclin expression. Furthermore, PKCß1 overexpression was associated with an enhancement of cell adhesion to fibronectin and with reduced migratory and invasive phenotypes. In agreement with these results, PANC1-PKCß1 cells showed an impaired ability to secrete proteolytic enzymes. We also found that PKCß1 overexpressing cells were more resistant to cell death induced by serum deprivation, an event associated with G0/G1 arrest and the modulation of PI3K/Akt and NF-κB pathways. Most notably, the overexpression of PKCß1 completely abolished the ability of PANC1 cells to induce tumors in nude mice. CONCLUSIONS: Our results established an important role for PKCß1 in PANC1 cells suggesting it would act as a suppressor of tumorigenic behavior in pancreatic cancer.
Assuntos
Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/etiologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/etiologia , Proteína Quinase C beta/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/patologia , Peptídeo Hidrolases/metabolismo , Proteína Quinase C beta/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR-dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5µM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30mg/kg b.w.) on tumor growth, MMP2 and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5µM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30mg/kg b.w.) activated c-Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression.
Assuntos
Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Neoplasias Mamárias Experimentais/induzido quimicamente , Invasividade Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologiaRESUMO
PURPOSE: Soy and its fermented products are considered functional foods. The study objective was to assess three functional food - a non-fermented soy product (NFP), fermented soy product (FSP), fermented soy product enriched with isoflavones (FI) - in terms of their ability to reduce the development of adenocarcinoma in mice, as well their ability on modulating immune system. METHODS: It was observed tumor volume and to verify correlations with the immune system it was measured levels of the cytokines IL-1ß and TNF-α produced by macrophages as well as IFN-γ produced by lymphocytes using ELISA test, and nitric oxide production by macrophages using Griess reagent. RESULTS: All products showed immunological activity, but FSP showed the most effective tumor containment, resulting in smallest tumor volumes. FI animals expressed larger amounts of nitric oxide and IL-1ß and exhibited larger tumor sizes than FSP and NFP animals. CONCLUSIONS: The results suggested that the ingestion of FSP was most efficient in tumor containment, possibly due to a positive modulation of the immune system by when Enterococcus faecium and Lactobacillus helveticus are added to the soy product.
Assuntos
Adenocarcinoma/dietoterapia , Antineoplásicos/farmacologia , Neoplasias da Mama/dietoterapia , Enterococcus faecium , Glycine max/microbiologia , Lactobacillus helveticus , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Fermentação , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Ribosome-inactivating proteins (RIP) have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. METHODS: The percentage of dendritic cells and CD4(+) and CD8(+) T cells in the spleen (flow cytometry), cytokines' release by PECs and splenocytes (ELISA) and nitric oxide production by PECs (Griess assay) were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 µg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey's post hoc test. RESULTS: Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN-γ and Th2 cytokines (IL-4 and IL-10), while IL-6 and TGF-ß levels were decreased. There was also an increase in macrophage's activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively). CONCLUSIONS: Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment.
Assuntos
Abrus/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Proteínas de Plantas/administração & dosagem , Proteínas Inativadoras de Ribossomos Tipo 2/administração & dosagem , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Células Th2/imunologiaRESUMO
Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. The present study evaluates tumor control and potential radiotoxicity of BNCT in an experimental model of liver metastasis. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT, boronophenylalanine (BPA) + neutron irradiation; Beam only, neutron irradiation; Sham, matched manipulation. The total absorbed dose administered with BPA-BNCT was 13 ± 3 Gy in tumor and 9 ± 2 Gy in healthy liver. Three weeks post-treatment, the tumor surface area post-treatment/pre-treatment ratio was 0.46 ± 0.20 for BPA-BNCT, 2.7 ± 1.8 for Beam only and 4.5 ± 3.1 for Sham. The pre-treatment tumor nodule mass of 48 ± 19 mg fell significantly to 19 ± 16 mg for BPA-BNCT, but rose significantly to 140 ± 106 mg for Beam only and to 346 ± 302 mg for Sham. For both end points, the differences between the BPA-BNCT group and each of the other groups were statistically significant (ANOVA). No clinical, macroscopic or histological normal liver radiotoxicity was observed. It is concluded that BPA-BNCT induced a significant remission of experimental colorectal tumor nodules in liver with no contributory liver toxicity.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Animais , Terapia por Captura de Nêutron de Boro/efeitos adversos , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Fígado/patologia , Fígado/efeitos da radiação , Masculino , Dosagem Radioterapêutica , Ratos , Resultado do TratamentoRESUMO
One of the major disadvantages of the current cancer therapy is the suppression of the immune system. Brazilian flora is considered one of the most diverse in the world and many plants were found to contain active constituents that can be valuable sources of new drugs. The plant Indigofera suffruticosa was studied to determine its potential to stimulate the immune system and also to be effective against tumour cells. We investigated the effects of the alkaloidal fraction and the pure alkaloid indigo obtained from I. suffruticosa on macrophage activation by measuring nitric oxide (NO) and tumour necrosis factor-α (TNF-α) production. Cytotoxic activity was also evaluated against the two tumour murine cells lines, LM2 (breast adenocarcinoma) and LP07 (lung adenocarcinoma). The alkaloidal fraction induced a high NO production and a moderated TNF-α release. The pure indigo demonstrated an elevated NO and TNF-α production. The fraction and the pure compound also exhibited cytotoxic activity against both adenocarcinoma cell lines and indigo showed the strongest cytotoxic activity with IC50 value of 0.89 µg mL⻹ against LM2 and 1.44 µg mL⻹ against LP07. Our results presented the immunostimulatory and cytotoxic activity of I. suffruticosa, enhancing macrophage function and therefore contributing to the host defence against tumours.
Assuntos
Adjuvantes Imunológicos/farmacologia , Citotoxinas/farmacologia , Indigofera/química , Extratos Vegetais/farmacologia , Adjuvantes Imunológicos/química , Alcaloides/farmacologia , Animais , Brasil , Linhagem Celular Tumoral , Citotoxinas/química , Descoberta de Drogas , Índigo Carmim , Indóis/farmacologia , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Angiogenesis, the growth of new capillaries from preexisting blood vessels, is a complex process involving endothelial cell (EC) activation, disruption of vascular basement membranes, and migration and proliferation of ECs. Glycan-mediated recognition has been proposed to play an instrumental role in mediating cell-cell and cell-matrix interactions. Galectins (Gal), a family of glycan-binding proteins with affinity for ß-galactosides and a conserved sequence motif, can decipher glycan-containing information and mediate cell-cell communication. Galectin-8 (Gal-8), a member of this family, is a bivalent "tandem-repeat"-type galectin, which possesses 2 CRDs connected by a linker peptide. Here, we show that Gal-8 is endowed with proangiogeneic properties. Functional assays revealed a critical role for this lectin in the regulation of capillary-tube formation and EC migration. Moreover, Matrigel, either supplemented with Gal-8 or vascular endothelial growth factor (VEGF), injected in mice resulted in induction of in vivo angiogenesis. Remarkably, Gal-8 was expressed both in the cytoplasm and nucleus in ECs of normal and tumor vessels. Furthermore, CD166 [activated leukocyte cell adhesion molecule (ALCAM)] was identified as a specific Gal-8-binding partner in normal vascular ECs. Collectively, these data provide the first evidence demonstrating an essential role for Gal-8 in the regulation of angiogenesis with critical implications in tumor biology.
Assuntos
Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Galectinas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Molécula de Adesão de Leucócito Ativado/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Colágeno , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Feminino , Galectinas/genética , Galectinas/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Cinética , Laminina , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Ligação Proteica , Proteoglicanas , Ratos , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
We previously demonstrated the therapeutic efficacy of different boron neutron capture therapy (BNCT) protocols in an experimental model of oral cancer. BNCT is based on the selective accumulation of (10)B carriers in a tumor followed by neutron irradiation. Within the context of exploring the potential therapeutic efficacy of BNCT for the treatment of liver metastases, the aim of the present study was to perform boron biodistribution studies in an experimental model of liver metastases in rats. Different boron compounds and administration conditions were assayed to determine which administration protocols would potentially be therapeutically useful in in vivo BNCT studies at the RA-3 nuclear reactor. A total of 70 BDIX rats were inoculated in the liver with syngeneic colon cancer cells DHD/K12/TRb to induce the development of subcapsular tumor nodules. Fourteen days post-inoculation, the animals were used for biodistribution studies. We evaluated a total of 11 administration protocols for the boron compounds boronophenylalanine (BPA) and GB-10 (Na(2)(10)B(10)H(10)), alone or combined at different dose levels and employing different administration routes. Tumor, normal tissue, and blood samples were processed for boron measurement by atomic emission spectroscopy. Six protocols proved potentially useful for BNCT studies in terms of absolute boron concentration in tumor and preferential uptake of boron by tumor tissue. Boron concentration values in tumor and normal tissues in the liver metastases model show it would be feasible to reach therapeutic BNCT doses in tumor without exceeding radiotolerance in normal tissue at the thermal neutron facility at RA-3.
Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Animais , Modelos Animais de Doenças , Feminino , Neoplasias Hepáticas/secundário , Masculino , RatosRESUMO
We investigated the use of a live, attenuated Salmonella enterica serovar Typhi vaccine strain as an antitumor immunotherapy. Mice bearing a subcutaneous tumor (LM3 mammary adenocarcinoma) were immunized on three occasions with S. Typhi strain CVD 915 by injection into the tumor, the peritumoral tissue and the draining lymph node areas; this procedure was termed Salmonella multiple treatment (Salmonella MT). Tumor-bearing mice subjected to the Salmonella MT exhibited reduced tumor growth, prolonged survival and reduced incidence of lung metastases, compared to untreated mice. We examined the mechanisms mediating this effect and found that Salmonella MT promoted an antitumor Th1-type response characterized by increased frequencies of IFN-γ-secreting CD4(+) T and CD8(+) T cells with reduction of regulatory T cells in tumor draining lymph nodes. The main cells infiltrating bacteria-treated tumors were activated neutrophils, which can exert an antitumor effect through the secretion of TNF-α. These results demonstrate for the first time the efficacy of an attenuated S. Typhi vaccine strain as a cancer immunotherapeutic agent. By potentiating the host antitumor immune response, this approach could be a powerful adjunct tool for cancer therapy.
Assuntos
Adenocarcinoma/terapia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Imunidade Celular , Imunoterapia/métodos , Ativação de Neutrófilo , Salmonella typhi/imunologia , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/prevenção & controle , Análise de Sobrevida , Células Th1/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologiaRESUMO
BACKGROUND: Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth. METHODS: Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. RESULTS: We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points. CONCLUSIONS: Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.