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1.
Gynecol Oncol ; 156(1): 251-259, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767187

RESUMO

The majority of endometrial cancers are detected early with a favourable prognosis. However, for patients with advanced disease, chemotherapy response rates and overall survival remains poor. The endometrial cancer population is typically elderly with multiple co-morbidities and aggressive cytotoxic therapy may be hazardous. Therefore, there is an urgent need to define optimal treatment strategies for advanced and recurrent disease and personalise therapy based on individual tumour and patient characteristics. Three-dimensional (3D) models that preserve the tumour microenvironment and tumour-stromal interactions are increasingly important for translational research with the advent of immunotherapy and molecularly targeted agents. 3D patient-relevant pre-clinical models in endometrial cancer include spheroids, patient-derived organoids, microfluidic systems, patient-derived xenografts and patient-derived explants. Here we present a review of available 3D modelling systems in endometrial cancers, highlighting their current use, advantages, disadvantages and applications to translational research with a focus on the power of the patient-derived explant platform.


Assuntos
Técnicas de Cultura de Células/métodos , Neoplasias do Endométrio/patologia , Animais , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Xenoenxertos , Humanos , Transplante de Neoplasias/métodos , Organoides/patologia , Esferoides Celulares/patologia , Pesquisa Médica Translacional/métodos
2.
PLoS One ; 14(12): e0227033, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887185

RESUMO

Mitochondrial disorders arise from defects in nuclear genes encoding enzymes of oxidative metabolism. Mutations of metabolic enzymes in somatic tissues can cause cancers due to oncometabolite accumulation. Paraganglioma and pheochromocytoma are examples, whose etiology and therapy are complicated by the absence of representative cell lines or animal models. These tumors can be driven by loss of the tricarboxylic acid cycle enzyme succinate dehydrogenase. We exploit the relationship between succinate accumulation, hypoxic signaling, egg-laying behavior, and morphology in C. elegans to create genetic and pharmacological models of succinate dehydrogenase loss disorders. With optimization, these models may enable future high-throughput screening efforts.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Caenorhabditis elegans/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Aminoácidos Dicarboxílicos/farmacologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/metabolismo , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Mutação , Paraganglioma/tratamento farmacológico , Paraganglioma/patologia , Feocromocitoma/tratamento farmacológico , Feocromocitoma/patologia , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Ácido Succínico/metabolismo
3.
J Enzyme Inhib Med Chem ; 34(1): 1722-1729, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31576761

RESUMO

In this study, new chalcone compounds having the chemical structure of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones (1-8) were synthesised and were characterised by 1H-NMR, 13 C-NMR, and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity results pointed out that compound 4, 6-[3-(4-trifluoromethylphenyl)-2-propenoyl]-3H-benzoxazol-2-one, showed the highest cytotoxicity (CC50) and potency-selectivity expression (PSE) value, and thus can be considered as a lead compound of this study. According to the CA inhibitory results, IC50 values of the compounds 1-8 towards hCA I were in the range of 29.74-69.57 µM, while they were in the range of 18.14 - 48.46 µM towards hCA II isoenzyme. Ki values of the compounds 1-8 towards hCA I were in the range of 28.37 ± 6.63-70.58 ± 6.67 µM towards hCA I isoenzyme and they were in the range of 10.85 ± 2.14 - 37.96 ± 2.36 µM towards hCA II isoenzyme.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzoxazóis/química , Benzoxazóis/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/toxicidade , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalcona/química , Criança , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
4.
Mar Drugs ; 17(10)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614563

RESUMO

Four new compounds were isolated from the Vietnamese marine sediment-derived fungus Aspergillus flocculosus, one aspyrone-related polyketide aspilactonol G (2), one meroterpenoid 12-epi-aspertetranone D (4), two drimane derivatives (7,9), together with five known metabolites (1,3,5,6,8,10). The structures of compounds 1-10 were established by NMR and MS techniques. The absolute stereoconfigurations of compounds 1 and 2 were determined by a modified Mosher's method. The absolute configurations of compounds 4 and 7 were established by a combination of analysis of ROESY data and coupling constants as well as biogenetic considerations. Compounds 7 and 8 exhibited cytotoxic activity toward human prostate cancer 22Rv1, human breast cancer MCF-7, and murine neuroblastoma Neuro-2a cells.


Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/metabolismo , Aspergillus/metabolismo , Produtos Biológicos/farmacologia , Fungos/metabolismo , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sedimentos Geológicos/microbiologia , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética/métodos , Biologia Marinha/métodos , Camundongos , Policetídeos/farmacologia , Sesquiterpenos/farmacologia
5.
J Cancer Res Clin Oncol ; 145(11): 2637-2647, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598791

RESUMO

PURPOSE: Malignant ascites (MA) is a common manifestation in advanced gastric cancer with peritoneal carcinomatosis and usually indicates a poor prognosis. However, lack of in vitro models that can faithfully recapitulate the characteristics of tumour cells in ascites hinders related researches. Tumour organoids have emerged as a robust in vitro model for tumour research and drug screening. Hence, we aimed to generate a 3-D in vitro organoid cultures from malignant ascites of gastric cancer for disease modelling and drug screening. METHODS: Eleven MADOs were generated from the MA tumour cells of gastric cancer patients. We made comparisons between MADOs and original MA tumour cells in histopathology by immunohistochemistry and genomics by whole-exome sequencing. In order to evaluate MADOs as functional in vitro disease models, we tested whether MADOs could be used for drug sensitivity screens. RESULTS: Eleven MADO cultures from human gastric cancer were established. MADOs demonstrated divergent growth characteristics and morphologies. MADO cultures preserve the histological architecture, genomic landscape of the corresponding MA tumour cells. MADOs exhibited heterogeneous responses to standard-of-care chemotherapeutics. CONCLUSIONS: We generated MADOs modelling characteristics and mutated genes of MA tumour cells. A broad range of intrinsic MADO response to conventional chemotherapeutics suggests MADOs are amenable to drug screening.


Assuntos
Antineoplásicos/farmacologia , Ascite/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Técnicas de Cultura de Órgãos/métodos , Organoides/patologia , Neoplasias Gástricas/patologia , Humanos , Técnicas In Vitro , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Células Tumorais Cultivadas , Sequenciamento Completo do Exoma
6.
Mar Drugs ; 17(8)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394844

RESUMO

Two new capnosane-based diterpenoids, flaccidenol A (1) and 7-epi-pavidolide D (2), two new cembranoids, flaccidodioxide (3) and flaccidodiol (4), and three known compounds 5 to 7 were characterized from the marine soft coral Klyxum flaccidum, collected off the coast of the island of Pratas. The structures of the new compounds were determined by extensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and spectroscopic data comparison with related structures. The rare capnosane diterpenoids were isolated herein from the genus Klyxum for the first time. The cytotoxicity of compounds 1 to 7 against the proliferation of a limited panel of cancer cell lines was assayed. The isolated diterpenoids also exhibited anti-inflammatory activity through suppression of superoxide anion generation and elastase release in the N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLF/CB)-stimulated human neutrophils. Furthermore, 1 and 7 also exhibited cytotoxicity toward the tested cancer cells, and 7 could effectively inhibit elastase release. It is worth noting that the biological activities of 7 are reported for the first time in this paper.


Assuntos
Antozoários/química , Fatores Biológicos/farmacologia , Diterpenos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocalasina B/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Espectroscopia de Ressonância Magnética/métodos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Elastase Pancreática/metabolismo , Superóxidos/metabolismo
7.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416180

RESUMO

Leukemias are neoplasms that affect hematopoietic cells, which are developed by genetic alterations (mutations) that lead to the loss of proliferation control mechanisms (maturation and/or cell death). The α4ß1 integrin receptor is a therapeutic target for inflammation, autoimmune diseases and lymphoid tumors. This study was carried out to search through the antagonists-based virtual screening for α4ß1 receptor. Initially, seventeen (17) structures were selected (based on the inhibitory activity values, IC50) and the structure with the best value was chosen as the pivot. The pharmacophoric pattern was determined from the online PharmaGist server and resulted in a model of score value equal to 97.940 with 15 pharmacophoric characteristics that were statistically evaluated via Pearson correlations, principal component analysis (PCA) and hierarchical clustering analysis (HCA). A refined model generated four pharmacophoric hypotheses totaling 1.478 structures set of Zinc_database. After, the pharmacokinetic, toxicological and biological activity predictions were realized comparing with pivot structure that resulted in five (ZINC72088291, ZINC68842860, ZINC14365931, ZINC09588345 and ZINC91247798) structures with optimal in silico predictions. Therefore, future studies are needed to confirm antitumor potential activity of molecules selected this work with in vitro and in vivo assays.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeos/química , Peptídeos/farmacologia , Análise por Conglomerados , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
8.
Genes (Basel) ; 10(9)2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466383

RESUMO

Breast cancer has become the most common cancer that leads to women's death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains challenging. In this work, we present a computational network biology approach to screen precision drugs for different breast cancer subtypes by considering the impact intensity of candidate drugs on the pathway crosstalk mediated by miRNAs. Firstly, we constructed and analyzed the subtype-specific risk pathway crosstalk networks mediated by miRNAs. Then, we evaluated 36 Food and Drug Administration (FDA)-approved anticancer drugs by quantifying their effects on these subtype-specific pathway crosstalk networks and combining with survival analysis. Finally, some first-line treatments of breast cancer, such as Paclitaxel and Vincristine, were optimized for each subtype. In particular, we performed precision screening of subtype-specific therapeutic drugs and also confirmed some novel drugs suitable for breast cancer treatment. For example, Sorafenib was applicable for the basal subtype treatment, Irinotecan was optimum for Her2 subtype treatment, Vemurafenib was suitable for the LumA subtype treatment, and Vorinostat could apply to LumB subtype treatment. In addition, the mechanism of these optimal therapeutic drugs in each subtype of breast cancer was further dissected. In summary, our study offers an effective way to screen precision drugs for various breast cancer subtype treatments. We also dissected the mechanism of optimal therapeutic drugs, which may provide novel insight into the precise treatment of cancer and promote researches on the mechanisms of action of drugs.


Assuntos
Neoplasias da Mama/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Redes Reguladoras de Genes , Genômica/métodos , MicroRNAs/genética , Medicina de Precisão/métodos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
9.
Surg Today ; 49(12): 1035-1043, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31267224

RESUMO

PURPOSE: We evaluated the clinical effectiveness of collagen gel droplet-embedded culture drug sensitivity tests (CD-DSTs) in predicting the efficacy of adjuvant chemo-therapeutic treatments for pancreatic cancer (PC). METHODS: The clinicopathological characteristics and prognoses of 22 PC patients who underwent CD-DST after pancreatectomy at Tohoku University between 2012 and 2016 were analyzed retrospectively. Eligibility criteria were resectable or borderline resectable PC, successful evaluation for 5-fluorouracil sensitivity by CD-DST, treatment with S-1 adjuvant chemotherapy, and no preoperative chemotherapy. RESULTS: The rate of successful evaluation by CD-DST was 52.3% in PC. The optimal T/C ratio, defined as the ratio of the number of cancer cells in the treatment group (T) to that in the control group (C), for 5-fluorouracil was 85% using receiver operating characteristic curve analysis. The sensitive group (T/C ratio < 85%; n = 11) had a better recurrence-free survival rate than the resistant group (T/C ratio ≥ 85%; n = 11; P = 0.029). A Cox proportional hazards regression model demonstrated that sensitivity to 5-fluorouracil was an independent predictor of recurrence on multivariate analysis (hazard ratio 3.28; 95.0% CI 1.20-9.84; P = 0.020). CONCLUSIONS: CD-DSTs helped to predict PC recurrence after S-1 adjuvant chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Quimioterapia Adjuvante , Colágeno , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fluoruracila/farmacologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Géis , Humanos , Masculino , Recidiva Local de Neoplasia , Ácido Oxônico/administração & dosagem , Ácido Oxônico/farmacologia , Neoplasias Pancreáticas/mortalidade , Valor Preditivo dos Testes , Estudos Retrospectivos , Taxa de Sobrevida , Tegafur/administração & dosagem , Tegafur/farmacologia , Resultado do Tratamento
10.
PLoS One ; 14(7): e0219517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291357

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality rate due to limited treatment options. Hence, the response of HCC to different cancer immunotherapies is being intensively investigated in clinical trials. Immune checkpoint blockers (ICB) show promising results, albeit for a minority of HCC patients. Mouse models are commonly used to evaluate new therapeutic agents or regimens. However, to make clinical translation more successful, better characterized preclinical models are required. We therefore extensively investigated two immune-competent orthotopic HCC mouse models, namely transplanted Hep-55.1c and transgenic iAST, with respect to morphological, immunological and genetic traits and evaluated both models' responsiveness to immunotherapies. Hep-55.1c tumors were characterized by rich fibrous stroma, high mutational load and pronounced immune cell infiltrates, all of which are features of immune-responsive tumors. These characteristics were less distinct in iAST tumors, though these were highly vascularized. Cell depletion revealed that CD8+ T cells from iAST mice do not affect tumor growth and are tumor tolerant. This corresponds to the failure of single and combined ICB targeting PD-1 and CTLA-4. In contrast, combining anti-PD-1 and anti-CTLA-4 showed significant antitumor efficacy in the Hep-55.1c mouse model. Collectively, our data comprehensively characterize two immune-competent HCC mouse models representing ICB responsive and refractory characteristics. Our characterization confirms these models to be suitable for preclinical investigation of novel cancer immunotherapy approaches that aim to either deepen preexisting immune responses or generate de novo immunity against the tumor.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Modelos Animais de Doenças , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antígenos Transformantes de Poliomavirus/genética , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral/transplante , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Nat Rev Drug Discov ; 18(9): 689-706, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292532

RESUMO

In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Neoplasias/tratamento farmacológico
12.
J Cancer Res Clin Oncol ; 145(8): 1949-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292714

RESUMO

PURPOSE: Efflux transporters of the adenosine triphosphate-binding cassette (ABC)-superfamily play an important role in the development of multidrug resistance (multidrug resistant; MDR) in cancer. The overexpression of these transporters can directly contribute to the failure of chemotherapeutic drugs. Several in vitro and in vivo models exist to screen for the efficacy of chemotherapeutic drugs against MDR cancer, specifically facilitated by efflux transporters. RESULTS: This article reviews a range of efflux transporter-based MDR models used to test the efficacy of compounds to overcome MDR in cancer. These models are classified as either in vitro or in vivo and are further categorised as the most basic, conventional models or more complex and advanced systems. Each model's origin, advantages and limitations, as well as specific efflux transporter-based MDR applications are discussed. Accordingly, future modifications to existing models or new research approaches are suggested to develop prototypes that closely resemble the true nature of multidrug resistant cancer in the human body. CONCLUSIONS: It is evident from this review that a combination of both in vitro and in vivo preclinical models can provide a better understanding of cancer itself, than using a single model only. However, there is still a clear lack of progression of these models from basic research to high-throughput clinical practice.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Técnicas de Cultura/métodos , Técnicas de Apoio para a Decisão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Especificidade de Órgãos , Seleção de Pacientes
13.
BMC Cancer ; 19(1): 718, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331301

RESUMO

BACKGROUND: Mouse clinical trials (MCTs) are becoming wildly used in pre-clinical oncology drug development, but a statistical framework is yet to be developed. In this study, we establish such as framework and provide general guidelines on the design, analysis and application of MCTs. METHODS: We systematically analyzed tumor growth data from a large collection of PDX, CDX and syngeneic mouse tumor models to evaluate multiple efficacy end points, and to introduce statistical methods for modeling MCTs. RESULTS: We established empirical quantitative relationships between mouse number and measurement accuracy for categorical and continuous efficacy endpoints, and showed that more mice are needed to achieve given accuracy for syngeneic models than for PDXs and CDXs. There is considerable disagreement between methods on calling drug responses as objective response. We then introduced linear mixed models (LMMs) to describe MCTs as clustered longitudinal studies, which explicitly model growth and drug response heterogeneities across mouse models and among mice within a mouse model. Case studies were used to demonstrate the advantages of LMMs in discovering biomarkers and exploring drug's mechanisms of action. We introduced additive frailty models to perform survival analysis on MCTs, which more accurately estimate hazard ratios by modeling the clustered mouse population. We performed computational simulations for LMMs and frailty models to generate statistical power curves, and showed that power is close for designs with similar total number of mice. Finally, we showed that MCTs can explain discrepant results in clinical trials. CONCLUSIONS: Methods proposed in this study can make the design and analysis of MCTs more rational, flexible and powerful, make MCTs a better tool in oncology research and drug development.


Assuntos
Ensaios Clínicos como Assunto/métodos , Desenvolvimento de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias/tratamento farmacológico , Animais , Biomarcadores Tumorais , Biópsia , Linhagem Celular Tumoral , Simulação por Computador , Modelos Animais de Doenças , Humanos , Isoenxertos , Modelos Lineares , Oncologia , Camundongos , Neoplasias/patologia , Intervalo Livre de Progressão , Projetos de Pesquisa , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Microbiol Biotechnol ; 29(8): 1212-1220, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31336431

RESUMO

The study of metabolomics in natural products using the diverse analytical instruments including GC-MS, LC-MS, and NMR is useful for the exploration of physiological and biological effects and the investigation of drug discovery and health functional foods. Cordyceps militaris has been very attractive to natural medicine as a traditional Chinese medicine, due to its various bioactive properties including anti-cancer and anti-oxidant effects. In this study, we analyzed the metabolite profile in 50% ethanol extracts of C. militaris fruit bodies from three development periods (growth period, matured period, and aging period) using 1H-NMR, and identified 44 metabolites, which are classified as 16 amino acids, 10 organic acids, 5 carbohydrates, 3 nucleotide derivatives, and 10 other compounds. Among the three development periods of the C. militaris fruit body, the aging period showed significantly higher levels of metabolites including cordycepin, mannitol (cordycepic acid), and ß-glucan. Interestingly, these bioactive metabolites are positively correlated with antitumor growth effect; the extract of the aging period showed significant inhibition of HepG2 hepatic cancer cell proliferation. These results showed that the aging period during the development of C. militaris fruit bodies was more highly enriched with bioactive metabolites that are associated with cancer cell growth inhibition.


Assuntos
Antineoplásicos/isolamento & purificação , Cordyceps/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desoxiadenosinas/análise , Descoberta de Drogas , Carpóforos/química , Células Hep G2/efeitos dos fármacos , Humanos , Manitol/análise , Medicina Tradicional Chinesa , beta-Glucanas/análise
15.
World J Gastroenterol ; 25(26): 3359-3369, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341361

RESUMO

Aptamers are a class of single oligonucleotide molecules (DNA or RNA) that are screened from random DNA or RNA oligonucleotide chain libraries by the systemic evolution of ligands by exponential enrichment technology. The selected aptamers are capable of specifically binding to different targeting molecules, which is achieved by the three-dimensional structure of aptamers. Aptamers are similar in function to monoclonal antibodies, and therefore, they are also referred to as "chemical antibodies". Due to their high affinity and specificity and low immunogenicity, aptamers are topics of intense interest in today's biological targeting research especially in tumor research. They not only have high potential for clinical advances in tumor targeting detection but also are highly promising as targeted tumor drug carriers for use in tumor therapy. Various experimental studies have shown that aptamer-based diagnostic and therapeutic methods for liver cancer have great potential for application. This paper summarizes the structure, characteristics, and screening methods of aptamers and reviews the recent research progress on nucleic acid aptamers in the targeted diagnosis and treatment of liver cancer.


Assuntos
Aptâmeros de Nucleotídeos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Detecção Precoce de Câncer/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Animais , Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos/química , Humanos , Microscopia Intravital/métodos , Ligantes , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Microscopia de Fluorescência/métodos , Sondas Moleculares/administração & dosagem , Sondas Moleculares/química , Estrutura Molecular , Sensibilidade e Especificidade
16.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1145-1154, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303583

RESUMO

Survivin (IAP proteins) is considered as a significant target for anticancer drug research owing to its upregulation in tumor cells to mediate resistance to apoptotic stimulus. The current study aimed to investigate phytochemicals as inhibitors of survivin with caspases to reactivate the functioning of caspases through molecular docking. The compounds namely 2(R), 4(R)-dihydroxypyrrolidine, 4-hydroxy-2-(4-methoxyphenyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide, 2,3-Diketo-L-gulonic acid, (3-hydroxy-2-octadeca-9,12-dienoyloxypropyl) octadecanoate, 2-[[4-[[4-[(4-formamido-1-methylimidazole-2-carbonyl)amino]-1-methylimidazole-2-carbonyl]amino]-1-methylimidazole-2-carbonyl]amino]ethyl-dimethylazanium, Picolinic acid and (2-Hydroxy-5-nitrophenyl) dihydrogen phosphate successfully bind inside the pocket of survivin. ADMETsar was used to evaluate the anticancer potential of selected compounds. These compounds can be proposed as effective inhibitors, disrupting the survivin-caspases interaction and reactivating the caspases function of apoptosis. The study might facilitate the development of cost-effective and natural drugs against cancer. However, further validation is essential for confirmation of its drug efficacy and bio-compatibility.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Compostos Fitoquímicos/farmacologia , Survivina/antagonistas & inibidores , Survivina/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Caspases/metabolismo , Simulação por Computador , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Compostos Fitoquímicos/farmacocinética , Compostos Fitoquímicos/toxicidade , Conformação Proteica , Survivina/metabolismo , Distribuição Tecidual
17.
Biosens Bioelectron ; 141: 111386, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220725

RESUMO

DNA methylation and histone deacetylation are key epigenetic processes involved in normal cellular function and tumorigenesis. Therapeutic strategies based on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors are currently in use and under development for the treatment of cancers. Genome-wide DNA methylation profiling has been proposed for use in disease diagnosis, and histone modification profiling for disease stratification will follow suit. However, whether epigenome sequencing technologies will be feasible for rapid clinic diagnosis and patient treatment monitoring remains to be seen, and alternative detection technologies will almost certainly be needed. Here we used electrochemical impedance spectroscopy (EIS) employing a graphene-based screen-printed electrode system to directly measure global DNA methylation and histone H3 acetylation to compare non-cancer and breast cancer cell lines. We demonstrated that whilst global methylation was not useful as a differential marker in the cellular systems tested, histone H3 acetylation was effective at higher chromatin levels. Using breast and endometrial cancer cell models, EIS was then used to monitor cellular responses to the DNMT and HDAC inhibitors 5-Aza-2'-deoxycytidine and suberoylanilide hydroxamic acid in vitro, and proved very effective at detecting global cellular responses to either treatment, indicating that this approach could be useful in following treatment response to epigenetic drugs. Moreover, this work reports the first combined analysis of two epigenetic markers using a unified graphene-based biosensor platform, demonstrating the potential for multiplex analysis of both methylation and acetylation on the same sample.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Metilases de Modificação do DNA/antagonistas & inibidores , Neoplasias do Endométrio/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Técnicas Biossensoriais/métodos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Espectroscopia Dielétrica/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias do Endométrio/genética , Feminino , Humanos
18.
BMC Cancer ; 19(1): 628, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238897

RESUMO

BACKGROUND: A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear. METHODS: We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation. RESULTS: Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses. CONCLUSIONS: This study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Ensaios de Triagem em Larga Escala , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Esferoides Celulares/patologia , Células Tumorais Cultivadas/patologia
19.
Int J Hematol ; 110(4): 482-489, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240558

RESUMO

Nilotinib is widely used for primary treatment of patients with chronic myelogenous leukemia (CML). We previously reported that use of an FRET-based drug sensitivity test at diagnosis efficiently predicts the response to treatment with imatinib or dasatinib. Here, we conducted a phase-II study to evaluate the efficacy and safety of nilotinib treatment and identify useful biomarkers, including results of the FRET-based drug sensitivity test, for predicting treatment response. Data from 42 patients were used in the analysis. Major molecular response (MMR), MR4, and MR4.5 rates at 12 months were 64.3, 42.9, and 28.6%, respectively. Grade 3/4 non-hematologic adverse events occurred in 11 patients (26.2%). The dose intensity of nilotinib (> 76.44%) and halving time (HT, < 13.312 days) were identified as significant factors for MMR at 12 months. However, when we focused on patients whose dose intensity of nilotinib was > 76.44%, the FRET-based drug sensitivity test became a predictive factor of MR4 achievement at 12 months. Our study reconfirmed the efficacy and safety of nilotinib treatment in CML patients. Moreover, our results suggest that the FRET-based drug sensitivity test is an independent predictor for achievement of MR4 in patients treated with a sufficient dose intensity of nilotinib.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Transferência Ressonante de Energia de Fluorescência/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Tempo , Adulto Jovem
20.
Mar Drugs ; 17(6)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234542

RESUMO

The previously reported 1-(2,4-dihydroxy-5-methylphenyl)ethan-1-one (1), (1'Z)-2-(1',5'-dimethylhexa-1',4'-dieny1)-5-methylbenzene-1,4-diol (2), and 1,8-epoxy-1(6),2,4,7,10-bisaborapentaen-4-ol (5) together with four new structures of aromatic bisabolane-related compounds (3, 4, 6, 7) were isolated from the marine sponge Myrmekioderma sp. Compounds 1, 2, and 5 were identified based on spectral data available in the literature. The structures of the four new compounds were experimentally established by 1D and 2D-NMR and (-)-HRESIMS spectral analysis. Cytotoxic and lipid-reducing activities of the isolated compounds were evaluated. None of the isolated compounds were active against the tested cancer cell lines; however, lipid-reducing activity was found for compounds 2-5 and 7 in the zebrafish Nile red fat metabolism assay. This class of compounds should be further explored for their suitability as possible agents for the treatment of lipid metabolic disorders and obesity.


Assuntos
Lipídeos/química , Poríferos/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HT29 , Humanos , Espectroscopia de Ressonância Magnética/métodos , Doenças Metabólicas/tratamento farmacológico , Peixe-Zebra
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