Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.029
Filtrar
1.
Life Sci ; 264: 118578, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33058910

RESUMO

Traditionally, Ehrlich's tumor is used in experimental oncology to investigate the therapeutic capacity of different synthetic chemotherapeutic agents or to evaluate the antitumoral activity of different substances of natural origin. However, the understanding of immune mechanisms during Ehrlich carcinogenesis is still limited. In this review, we seek to describe the immune response during Ehrlich's tumor growth, and natural response without the influence of pharmacological administration, immunotherapies or concomitant challenges. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review was carried out that included experimental trials with mice challenged with Ehrlich's tumor. The research was carried out in three databases including MEDLINE/PubMed, Scopus, Latin American and Caribbean Literature in Health Sciences (LILACS). The searches resulted in 913 papers being found, of which 55 articles were considered eligible, and of these 55, 29 were selected for analysis. Findings indicate that there is an increase in the expression of M2 and T Helper (TH2) macrophages and of the cytokines IL-17, IL-1B, IL-6 and PGE in the ascitic form of Ehrlich. These phenotypic expressions are also found in ascitic neoplasms in humans. Ehrlich's solid tumor was characterized by increased expression of CD4, CD8, neutrophils and TNF-a, Foxp3 + and Qa-2 +, and these characteristics are analogous to human breasts cancers. It is our understanding that further studies are needed to assess the immune mechanisms in Ehrlich's tumor, since these findings can be used to improve cancer treatments that are analogous to Ehrlich's tumor.


Assuntos
Imunidade Adaptativa/fisiologia , Carcinoma de Ehrlich/imunologia , Carcinoma de Ehrlich/patologia , Imunidade Inata/fisiologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/fisiologia , Imunidade Inata/efeitos dos fármacos , Camundongos , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia
2.
Chem Biol Interact ; 333: 109330, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33245929

RESUMO

AIM: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties. METHODS: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-ß (TGF-ß), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83+, CD8+ and CD166+ cell percentage were measured in lung tissue. RESULTS: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-ß, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83+ cells, CD8+ cells and increased number of CD166+ cells. CONCLUSION: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.


Assuntos
Benzo(a)pireno/farmacologia , Carcinogênese/efeitos dos fármacos , Imunossupressores/farmacologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Animais , Antígenos CD/metabolismo , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-12/genética , Camundongos , Análise de Sobrevida , Fator de Crescimento Transformador beta/genética , Carga Tumoral/efeitos dos fármacos
3.
Int J Nanomedicine ; 15: 9283-9299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262588

RESUMO

Aim: The present study focuses on the development and evaluation of the resveratrol (RV)-loaded cationic solid lipid nanoparticles (RV-c-SLNs) for the management of hepatocellular carcinoma (HCC). Materials and Methods: Optimization of formulation was performed using factorial design, and further in vitro drug release, cytotoxicity, biodistribution, in vivo preclinical, and biochemical evaluation were carried out. Results: The optimized formulation exhibited uniform size, homogeneous disparity, positive zeta potential, and stability over 12-week storage at 25°C/60% RH. The in vitro drug release and cytotoxicity study showed 60% drug release within the first 6 hours and comparatively higher cytotoxicity on HepG2 cell line by resveratrol-solid lipid nanoparticle (RV-SLN) as compared to the RV solution. In addition, an anticancer action and biodistribution study on a rat model of HCC showed significant reduction of tumor volume and higher accumulation in the tumor tissue from RV-c-SLN (P<0.01) over RV solution and RV-SLN. Furthermore, RV-c-SLN showed significant down-regulation in the levels of pro-inflammatory cytokines and balancing of antioxidant enzymes. Histopathological investigation showed reduced occurrence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessels inflammation, and cell swelling. Conclusion: Overall, the obtained results construed that RV-c-SLN with improved antitumor activity as clearly evident from in vitro, in vivo, and biochemical investigations.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Resveratrol/uso terapêutico , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Cátions , Morte Celular/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Nanopartículas/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Tamanho da Partícula , Ratos Wistar , Resveratrol/farmacologia , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
4.
Cochrane Database Syst Rev ; 11: CD008994, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226133

RESUMO

BACKGROUND: Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. OBJECTIVES: To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. SELECTION CRITERIA: All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. AUTHORS' CONCLUSIONS: Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Dispositivos Intrauterinos Medicados , Leiomioma/tratamento farmacológico , Progestinas/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Adulto , Viés , Anticoncepcionais Orais/administração & dosagem , Desogestrel/administração & dosagem , Feminino , Gosserrelina/administração & dosagem , Humanos , Leiomioma/patologia , Leuprolida/administração & dosagem , Levanogestrel/administração & dosagem , Linestrenol/administração & dosagem , Acetato de Medroxiprogesterona/administração & dosagem , Menstruação/efeitos dos fármacos , Pessoa de Meia-Idade , Nandrolona/administração & dosagem , Nandrolona/análogos & derivados , Acetato de Noretindrona/administração & dosagem , Pré-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Carga Tumoral/efeitos dos fármacos , Neoplasias Uterinas/patologia
5.
Nucleic Acids Res ; 48(21): 12234-12251, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33211885

RESUMO

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.


Assuntos
Neoplasias do Colo/tratamento farmacológico , DNA Glicosilases/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Poli(ADP-Ribose) Polimerase-1/imunologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Dano ao DNA , DNA Glicosilases/antagonistas & inibidores , DNA Glicosilases/metabolismo , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanina/análogos & derivados , Guanina/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Estresse Oxidativo , Poli(ADP-Ribose) Polimerase-1/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 40(11): 6083-6091, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109546

RESUMO

BACKGROUND/AIM: The aim of the study was to determine if oral recombinant methioninase (o-rMETase) can sensitize an orthotopic bladder tumor in nude mice to low-dose cisplatinum (CDDP). MATERIALS AND METHODS: The green fluorescent protein (GFP)-expressing UM-UC-3-GFP bladder cancer was surgically orthotopically implanted (SOI) to the bladder in nude mice. The treatment was initiated when the primary tumor volume reached 100 mm3 Mice were assigned to 3 groups: G1: Saline vehicle (0.1 ml per mouse, oral, twice per day); G2: low-dose CDDP (0.5 mg/kg, intraperitoneal twice per week); G3: o-rMETase + low-dose CDDP (100 units per mouse, oral, twice per day + 0.5 mg/kg, intraperitoneal twice per week, respectively). Tumor volume and body weight were measured twice per week. The expression of Ki-67 was detected by immunohistochemistry to evaluate cell proliferation. RESULTS: The combination of o-rMETase and low-dose CDDP increased inhibition efficacy compared to low-dose CDDP monotherapy, on primary-tumor growth (p=0.032) and metastasis (p=0.002). CONCLUSION: The combination of o-rMETase with low-dose CDDP has future clinical potential for bladder cancer.


Assuntos
Liases de Carbono-Enxofre/uso terapêutico , Cisplatino/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Liases de Carbono-Enxofre/administração & dosagem , Liases de Carbono-Enxofre/farmacologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos Nus , Metástase Neoplásica , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Carga Tumoral/efeitos dos fármacos
7.
J Cancer Res Ther ; 16(4): 788-792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930119

RESUMO

Context: Spirometry is an important tool to monitor treatment response in diseases such as chronic obstructive pulmonary disease and asthma. However, there is lack of evidence to support its application to evaluate response to chemotherapy in advanced lung cancer. It might be a useful adjunct to the imaging-based response evaluation which lacks functional assessment of lungs. Aims: The study was conducted to evaluate the change in spirometry in lung cancer patients after chemotherapy and to find its correlation with change in physical tumor size. Subjects and Methods: Sixty-two advanced lung cancer patients who were eligible for palliative chemotherapy were enrolled. Baseline tumor size evaluation using Response Evaluation Criteria in Solid Tumor (RECIST)-based scoring system, and spirometry was done. Four cycles of double agent (platinum doublets) chemotherapy were administered, after which treatment response was evaluated. Repeat spirometry was analyzed and correlated with changes in physical tumor size. Results: Twenty-five patients showed a response (all partial response) to four cycles of chemotherapy. Small cell carcinoma showed a better response rate than non-small cell carcinoma (78% vs. 39%). There was statistically significant improvement in forced expiratory volume in 1 (FEV1) (P = 0.01) and forced vital capacity (P = 0.03) in responders as compared to nonresponders. Change in FEV1 showed a statistically significant correlation with the change in tumor size (RECIST score) (r = -0.34; P = 0.04). Conclusions: Improvement in spirometry correlates with the tumor response as judged using RECIST criteria after chemotherapy. Further studies with bigger sample size are required to consolidate the results.


Assuntos
Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Estudos Prospectivos , Testes de Função Respiratória/métodos , Espirometria/métodos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
8.
Int J Nanomedicine ; 15: 6311-6324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922003

RESUMO

Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Hialuronoglucosaminidase/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/patologia , Polímeros/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
9.
Nat Commun ; 11(1): 4527, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913197

RESUMO

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Cultura Primária de Células , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA-Seq , Estudos Retrospectivos , Esferoides Celulares , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Supressora de Tumor p53/genética , Microtomografia por Raio-X
10.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 11(1): 3858, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737343

RESUMO

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.


Assuntos
Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/farmacologia , Linfoma/terapia , Estruturas Metalorgânicas/farmacologia , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citotoxicidade Imunológica , Composição de Medicamentos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Estruturas Metalorgânicas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor de Morte Celular Programada 1/imunologia , Dióxido de Silício/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619553

RESUMO

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Carga Tumoral/fisiologia
13.
Br J Radiol ; 93(1115): 20200257, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706980

RESUMO

OBJECTIVE: To evaluate the multiparametric MRI in predicting chemotherapy response in pathologically proven cases of osteosarcoma and Ewing's sarcoma. Correlation between the tumor size changes and internal breakdown using RECIST 1.1, modified RECIST, quantitative apparent diffusion coefficient (ADC) and tumor volume as well as dynamic contrast-enhanced MRI (DCE-MRI). METHODS: The study included 104 patients pathologically proved osteosarcoma (53) and Ewing`s sarcoma (51) underwent MRI examinations; before and after chemotherapy. All patients were assessed using the RECIST 1.1 criteria, m-RECIST, quantitative ADC, and tumor volume evaluation. 21 patients underwent DCE-MRI curve type with quantitative parameters. Correlation between the different evaluations was carried out. Results were correlated with the post-operative pathology in 42 patients who underwent surgery and for statistical evaluation, Those patients were classified into responders (≥90% necrosis) and non-responders (<90% necrosis). RESULTS: The initial mean ADC of 104 patients of osteosarcoma and Ewing's sarcoma (0.90 ± 0.29) and (0.71 ± 0.16) respectively, differed significantly from that after treatment (1.62 ± 0.46) and (1.6 ± 0.39) respectively with (p<0.001).ADC variations (ADC%) in the non-progressive group were higher than those of the progressive group (128.3 ± 63.49 vs 36.34 ± 78.7) % with (p<0.001).ADC values and ADC variations were inversely correlated with morphologic changes, regardless of the effectiveness of chemotherapy expressed as changes in tumor size based on (RECIST 1.1, RECIST, and 3D volume). Linear regression analysis revealed a Pearson correlation coefficient of r=-0.427, -0.498 and -0.408, respectively with (p<0.001).An increase in the ADC value was not always associated with a reduction in tumor volume. The disease control rate (defined as the percentage of CR+PR+SD patients) was 89.4% and 93.9% according to RECIST 1.1 and m-RECIST respectively.42 out of the 104 patients had postsurgical histological evaluation as regards the chemotherapeutic response divided into two groups. ADC values showed a statistically significant difference between Group A and Group B being more evident with minimum ADC% (p<0.001). CONCLUSION: Quantitative diffusion-weighted imaging with ADC mapping and ADC % after chemotherapy allows a detailed analysis of the treatment response in osteosarcoma and Ewing's sarcoma. The therapeutic response can be underestimated using RECIST 1.1, so the modified RECIST should be also considered. ADVANCES IN KNOWLEDGE: Quantitative ADC especially ADC% provided an accurate non-invasive tool in the assessment of post-therapeutic cases of osteosarcoma and Ewing's sarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética Multiparamétrica , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Área Sob a Curva , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Meios de Contraste , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Estudos Prospectivos , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Adulto Jovem
14.
PLoS One ; 15(7): e0236350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687531

RESUMO

PURPOSE: We evaluated that early metabolic response determined by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) during radiotherapy (RT), predicts outcomes in non-small cell lung cancer. MATERIAL AND METHODS: Twenty-eight patients evaluated using pretreatment 18F-FDG-PET/CT (PETpre) and interim 18F-FDG-PET/CT (PETinterim) after 11 fractions of RT were retrospectively reviewed. Maximum standardized uptake value (SUVmax) was calculated for primary lesion. Predictive value of gross tumor volume (ΔGTV) and SUVmax (ΔSUVmax) changes was evaluated for locoregional control (LRC), distant failure (DF), and overall survival (OS). Metabolic responders were patients with ΔSUVmax >40%. RESULTS: Metabolic responders showed better trends in 1-year LRC (90.9%) than non-responders (47.1%) (p = 0.086). Patients with large GTVpre (≥120 cc) demonstrated poor LRC (hazard ratio 4.14, p = 0.022), while metabolic non-responders with small GTVpre (<120 cc) and metabolic responders with large GTVpre both had 1-year LRC rates of 75.0%. Reduction of 25% in GTV was not associated with LRC; however, metabolic responders without a GTV response showed better 1-year LRC (83.3%) than metabolic non-responders with a reduction in GTV (42.9%). Metabolic responders showed lower 1-year DF (16.7%) than non-responders (50.0%) (p = 0.025). An ΔSUVmax threshold of 40% yielded accuracy of 64% for predicting LRC, 75% for DF, and 54% for OS. However, ΔGTV > 25% demonstrated inferior diagnostic values than metabolic response. CONCLUSIONS: Changes in tumor metabolism diagnosed using PETinterim during RT better predicted treatment responses, recurrences, and prognosis than other factors historically used.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Neoplasias Pulmonares/terapia , Pulmão/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Fluordesoxiglucose F18/administração & dosagem , Seguimentos , Humanos , Pulmão/patologia , Pulmão/efeitos da radiação , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação
15.
Ann Surg ; 272(2): 311-318, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675544

RESUMO

OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/terapia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Institutos de Câncer , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Glicólise/efeitos dos fármacos , Glicólise/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Texas , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação
16.
Sci Rep ; 10(1): 9223, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514049

RESUMO

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/diagnóstico por imagem , Astrocitoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Processamento de Imagem Assistida por Computador , Camundongos , Camundongos Endogâmicos C57BL , Gradação de Tumores , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transplante Heterólogo , Carga Tumoral/efeitos dos fármacos
17.
J Cancer Res Ther ; 16(2): 356-364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474524

RESUMO

Objective: This study aimed to classify hepatocellular carcinomas (HCCs) according to their diameter using statistic technology and evaluate the prognosis of the classified groups after the combined use of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). Materials and Methods: Electronic medical records of 128 consecutive patients who underwent TACE-RFA as the initial treatment for HCC from January 2010 to April 2018 were retrospectively analyzed. TACE was initially performed with subsequent RFA performed after 3-7 days. The decision tree model was used to classify overall survival (OS), progression-free survival (PFS), local recurrence rate (LRR), and treatment complications in HCC. Results: The tumors were divided into three groups of sizes ≤2.9 cm, 2.9-4.8 cm, and >4.8 cm. The group of tumors >4.8 cm showed inferior OS, PFS, and LRR than the other two groups (P < 0.05) on long-term follow-up but not in thefirst 6 months (P > 0.05). The groups of tumors ≤2.9 cm and 2.9-4.8 cm showed no statistically significant difference in OS, PFS, and LRR (P > 0.05). Conclusions: The cutoff points of 2.9 and 4.8 cm were achieved using the objective decision tree model rather than the artificial division of 3 and 5 cm. The prognosis was not significantly different between the groups of tumors ≤2.9 cm and 2.9-4.8 cm, and the prognosis of the two groups was better than the group of tumors >4.8 cm in the long-term follow-up but not in thefirst 6 months.


Assuntos
Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/patologia , Ablação por Cateter/mortalidade , Quimioembolização Terapêutica/mortalidade , Carga Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/terapia , Ablação por Cateter/métodos , Quimioembolização Terapêutica/métodos , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Biochem Pharmacol ; 178: 114089, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32533968

RESUMO

Recently, we and other groups revealed that aberrant expression of Kv10.1 channel, a voltage-gated potassium ion channel, contributes to a variety of tumorigenesis process.Potent and selective inhibitor of Kv10.1 is urgently needed, both as pharmacological tools for studying the physiological functions of this enigmatic channel and as potential leads for development of anti-tumor drugs. In this study, Procyanidin B1, a natural compound extracted from the grape seed, was identified as a potent, specific inhibitor, which can inhibit the Kv10.1 channel in a concentration-dependent manner (IC50 = 10.38 ± 0.87 µM), but has negligible effects on other potassium channels, including Kir2.1, HERG or KCNQ1. It was demonstrated that Procyanidin B1 directly binds to Kv10.1 channel and inhibits its currents, without increasing intracellular Ca2+. Further, three amino acids, I550, T552, and Q557 in the C-linker domain of Kv10.1 were found critical for forming the binding pocket of Procyanidin B1 with Kv10.1 channel.In addition, Procyanidin B1 inhibits migration and proliferation of liver cancer cells (HuH-7 cells, HepG2 cells) through inhibiting Kv10.1, but not in Kv10.1 negatively expressed cell lines. Next, we assayed the tumor suppressing effect of Procyanidin B1 on cell line-derived xenograft mouse model. Our data showed that 15 mg/kg Procyanidin B1 can significantly suppress the growth of the tumor (HepG2) with an inhibition rate of about 60.25%. Compared with cisplatin, Procyanidin B1 has no side effect on the normal metabolismof the mice. The present work indicated that Procyanidin B1 is a proming liver cancer anti-tumor drug, and also confirmed that Kv10.1 can serve as a potential, tumor-specific drug target.


Assuntos
Biflavonoides/farmacologia , Carcinoma Hepatocelular/metabolismo , Catequina/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Neoplasias Hepáticas/metabolismo , Proantocianidinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Biflavonoides/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Catequina/uso terapêutico , Canais de Potássio Éter-A-Go-Go/química , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/dietoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proantocianidinas/uso terapêutico , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Carga Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
J Leukoc Biol ; 107(6): 981-991, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32449229

RESUMO

Immune checkpoint inhibitors are profoundly transforming cancer therapy, but response rates vary widely. The efficacy of checkpoint inhibitors, such as anti-programmed death receptor-1 (anti-PD-1), might be increased by combination therapies. TNFR2 has emerged as a new target due to its massive expression on highly immunosuppressive regulatory T cells (Tregs) in the microenvironment and on certain tumor cells. In murine colon cancer models CT26 and MC38, we evaluated the efficacy of a new anti-TNFR2 antibody alone or in combination with anti-PD-1 therapy. Tumor-bearing mice were treated with placebo, anti-PD-1 alone, anti-TNFR2 alone, or combination anti-PD-1 and anti-TNFR2. We found that combination therapy had the greatest efficacy by complete tumor regression and elimination (cure) in 65-70% of animals. The next most effective therapy was anti-TNFR2 alone (20-50% cured), whereas the least effective was anti-PD-1 alone (10-25% cured). The mode of action, according to in vivo and in vitro methods including FACS analysis, was by killing immunosuppressive Tregs in the tumor microenvironment and increasing the ratio of CD8+ T effectors (Teffs) to Tregs. We also found that sequence of antibody delivery altered outcome. The two most effective sequences were simultaneous delivery (70% cured) followed by anti-TNFR2 preceding anti-PD-1 (40% cured), and the least effective was by anti-PD-1 preceding anti-TNFR2 (10% cured). We conclude that anti-PD-1 is best enhanced by simultaneous administration with anti-TNFR2, and anti-TNFR2 alone may be potentially useful strategy for those do not respond to, or cannot tolerate, anti-PD-1 or other checkpoint inhibitors.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias do Colo/terapia , Regulação Neoplásica da Expressão Gênica , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/química , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Terapia Combinada/métodos , Esquema de Medicação , Humanos , Imunoterapia/métodos , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Nanomedicine ; 15: 3193-3206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440118

RESUMO

Background: Certain patients with triple-negative breast cancer cannot tolerate the serious adverse effects of cytotoxic chemotherapy agents, which significantly affect the disease prognosis. Purpose: Research into the combined use of photosensitizers and non-cytotoxic antineoplastic drugs for the safe treatment of triple-negative breast cancer is vital. Methods: In this study, the photosensitizer indocyanine green and the natural drug parthenolide were co-loaded into thermosensitive liposomes. Under a near-infrared irradiation, indocyanine green reached excitation levels, releasing heat, and the liposome underwent a phase transition, releasing the drug were researched. Results: Thus, indocyanine green and parthenolide exert synergistic antineoplastic effects. In the nude mice xenograft MDA-MB-231 tumor model, the tumor inhibition rate of indocyanine green-parthenolide thermosensitive liposomes was approximately 2.08-fold than that of paclitaxel and demonstrated a good initial safety evaluation. Conclusion: Photosensitizers and non-cytotoxic antineoplastic agents in combination with nanoscale carriers should be further investigated for the treatment of tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Verde de Indocianina/uso terapêutico , Sesquiterpenos/uso terapêutico , Temperatura , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Hidrodinâmica , Verde de Indocianina/administração & dosagem , Verde de Indocianina/farmacologia , Lipossomos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA