RESUMEN
An artificial double tandem tumor-specific promoter based on survivin and human telomerase reverse transcriptase gene promoters was constructed. Studies in in vitro and ex vivo therapeutic systems showed that the designed promoter exhibits a high activity in tumor cells, which is comparable to the activity of the CMV constitutive promoter.
Asunto(s)
Citomegalovirus/genética , Terapia Genética , Proteínas Inhibidoras de la Apoptosis/genética , Neoplasias/genética , Neoplasias/terapia , Regiones Promotoras Genéticas , Línea Celular Tumoral , Humanos , Neoplasias/patología , SurvivinRESUMEN
In this study, we evaluated the antitumor activity of a gene therapy complex in which the tumor-specific control of the expression of the effector suicide gene FCU1 was performed using a two-vector system based on the site-specific Cre-LoxP recombinase system. The complex of interest showed a high therapeutic potential in a mouse colon adenocarcinoma model.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Genes Transgénicos Suicidas , Vectores Genéticos , Integrasas , Neoplasias Experimentales , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Animales , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/terapia , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Integrasas/genética , Integrasas/metabolismo , Ratones Endogámicos BALB C , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/terapiaRESUMEN
Despite substantial progress in understanding the mechanisms of carcinogenesis and fighting oncology diseases, cancer mortality remains rather high. Therefore, there is a striving to reduce this mortality to the level determined by endogenous biological factors. The review analyzes the mutations that lead to cell malignant transformation and describes the contribution that self-renewal of adult tissues makes to tumorigenesis. Cancer progression is considered as a development of a complicated system where cells mutate, evolve, and are subject to selection. Cancer paradoxes are described in conclusion.
Asunto(s)
Transformación Celular Neoplásica/genética , Mutagénesis , Mutación , Neoplasias/genética , Animales , Transformación Celular Neoplásica/metabolismo , Humanos , Neoplasias/metabolismoRESUMEN
This review was devoted to the use of the versatile component oftumoral stroma (fibroblast activation protein, FAP) as a target of the versatile tumor therapy. The tumor is a coevolution system, which includes the microenvironment or reactive stroma differing from the normal tissue by the phenotypic and genotypic features. Important elements of the tumor microenvironment are cancer-associated fibroblasts (CAFs), which contain typical marker FAP (serine proteinase with the enzymatic activity of dipeptidyl peptidase and endopeptidase). According to the literature, more than 90% of tumors contain FAP-positive activated fibroblasts. FAP is virtually absent in normal tissues, but it is present in the embryonic and tumor tissues, which makes it a selective and versatile model. In this work, basic approaches to affecting the CAF using FAP as a target were discussed. The use of FAP as a target provides an important advantage: its proteolytic activity can be used along with the protein-targeted agents. The main directions in the therapeutic use of FAP were discussed in this work.
Asunto(s)
Biomarcadores de Tumor , Gelatinasas , Proteínas de la Membrana , Proteínas de Neoplasias , Neoplasias , Serina Endopeptidasas , Microambiente Tumoral , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Endopeptidasas , Fibroblastos/metabolismo , Fibroblastos/patología , Gelatinasas/genética , Gelatinasas/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
The review discusses the causes of multiple failures in cancer treatment, which might primarily result from the excessive variability of cancer genomes. They are capable of changing their spatial and temporal architecture during tumor development. The key reasons of irreproducibility of biomedical data and the presumable means for improvement of therapeutic results aiming at targeting the most stable tumor traits are suggested.
Asunto(s)
Biología Molecular , Neoplasias/genética , Animales , Humanos , Neoplasias/patología , Neoplasias/terapia , Reproducibilidad de los ResultadosRESUMEN
The fibroblast activation protein (FAP) is selectively expressed in cancer-associated fibroblasts (CAFs) and facilitates tumor progression, which makes this protein an attractive therapeutic target. There are difficulties in obtaining CAFs for studying the function and suppression of FAP. In this work, the expression level of FAP was determined by PCR assay in 25 human cell lines and 8 surgical samples of tumor stroma. The expression of FAP was observed in all tumor stroma samples and in four cell lines: NGP-127, SJCRH30, SJSA-1, and A375. The level of FAP expression in NGP-127, SJCRH30, and SJSA-1 lines as well as in CAFs of patients was comparable, which makes these cell lines a possible model for studying FAP.
Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Gelatinasas/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias/metabolismo , Serina Endopeptidasas/metabolismo , Western Blotting , Línea Celular Tumoral , Endopeptidasas , Expresión Génica , Humanos , Neoplasias/cirugía , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Células del Estroma/metabolismoRESUMEN
Antitumor efficacy of the combined suicide gene therapy and radiotherapy was studied on the model of CT26 murine colon adenocarcinoma. CMV-FCU1-IRES-mGM-CSF-pGL3 construct with PEG-PEI-TAT (FCU1-mGM/5-FC) block copolymer as a vector was used for intratumoral administration. Tumors were irradiated with a single 5 Gy dose. The efficacy was evaluated according to the grade of tumor growth inhibition (T/C) and lifespan of the animals. Pronounced antitumor activity of the combined use of FCU1-mGM/5-FC system with radiotherapy on the background of prolonged lifespan and the synergism of the applied methods was revealed.
Asunto(s)
Adenocarcinoma/terapia , Neoplasias del Colon/terapia , Genes Transgénicos Suicidas , Terapia Genética/métodos , Adenocarcinoma/patología , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Neoplasias del Colon/patología , Terapia Combinada/métodos , Citomegalovirus/genética , Flucitosina/administración & dosificación , Fluorouracilo/administración & dosificación , Vectores Genéticos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Ratones Endogámicos BALB C , Clasificación del Tumor , Trasplante de Neoplasias , Resultado del Tratamiento , Carga TumoralRESUMEN
Enhancers make up a huge class of genome regulatory elements that play an important role in the formation and maintenance of specific patterns of gene transcriptional activity in all types of cells. In recent years, high-throughput methods for the genome-wide epigenetic analysis of chromatin have made it possible to identify structural and functional features of enhancers and their role in the spatial and functional organization of the genome and in the formation and maintenance of cell identity, as well as in the pathogenesis of certain diseases. Special attention has been focused on genome regions called super-enhancers, or stretch enhancers, which consist of clusters of elements with properties of classic enhancers. This review considers current data on specific properties of super-enhancers and their role in the formation of interconnected autoregulatory circuits with positive feedback that regulates the most important genes, the activity of which underlies the formation and maintenance of specialized cellular functions.
Asunto(s)
Carcinogénesis/genética , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes Reguladores , Animales , Carcinogénesis/metabolismo , HumanosRESUMEN
Recent data on adult stem cells are reviewed. According to the present dominant paradigm, it is most probable that cancer predisposition arises or cancer is initiated in these cells.
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Células Madre Adultas/metabolismo , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Adultas/patología , Animales , Susceptibilidad a Enfermedades , Humanos , Neoplasias/genética , Neoplasias/patología , Células Madre Neoplásicas/patologíaRESUMEN
Recent data on adult stem cells are reviewed. According to the present dominant paradigm, it is most probable that cancer predisposition arises or cancer is initiated in these cells.
Asunto(s)
Células Madre Adultas/metabolismo , Transformación Celular Neoplásica/genética , Células Madre Neoplásicas/metabolismo , Células Madre Adultas/citología , Animales , Linaje de la Célula , Evolución Clonal , ADN de Neoplasias/genética , Humanos , Células Madre Neoplásicas/patologíaRESUMEN
In preparation of the therapeutic genetic constructs aimed to the gene-programmed enzymatic transformation of the non-toxic prodrug into toxin within cancer cells the right choice of regulatory elements (promoters and enhancers) is essential. This is widely accepted that the efficiency of the gene therapy constructions is dependent, in particular, on the strength of promoters driving the expression of the therapeutic genes. In this work we demonstrated, using the melanoma-specific promoters and enhancers of human melanoma inhibitory activity and mouse tyrosinase gene, that for the development of cytotoxic effect the promoter strength is not of primary importance. In the case of HSVtk, coding for the herpes simplex virus thymidine kinase, and FCU1, coding for cytosine deaminase/uracil phosphoribosyltransferase hybrid protein genes, their cytotoxic activity was determined by the quantity of the added prodrug.
Asunto(s)
Citosina Desaminasa/genética , Terapia Genética , Melanoma Experimental/genética , Pentosiltransferasa/genética , Animales , Citosina Desaminasa/uso terapéutico , Genes Transgénicos Suicidas , Humanos , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Pentosiltransferasa/uso terapéutico , Profármacos/uso terapéutico , Regiones Promotoras Genéticas , Simplexvirus/enzimología , Simplexvirus/genéticaRESUMEN
Melanoma is one of the most aggressive tumors. It develops from pigment-forming cells (melanocytes) and results in a high number of lethal outcomes. The use of genetic constructs with the ability to specifically kill melanoma cells, but not normal cells, might increase the lifespan of patients, as well as improve their quality of life. One of the methods to achieve a selective impact for therapeutic genes on cancer cells is to utilize a transcriptional control mechanism using promoters that are specifically activated only in cancerous cells. In this review, promoters of the genes that are preferentially expressed in melanoma cells are described. These promoters, and other highly melanoma-specific regulatory elements, reduce the unspecific expression of therapeutic genes in normal tissues. Moreover, cancer-specific promoters and their elements are advantageous for the development of universal anticancer drugs. Examples of the use of double promoters that have a high potential as instruments in cancer gene therapy are also given in this review.