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Pesquisa : G05.360.340.024.340.825.500 [Categoria DeCS]
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[PMID]:29353670
[Au] Autor:Liu Y; Zhu P; Huang Z; Zhou L; Shi P
[Ad] Endereço:State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China; Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
[Ti] Título:Simultaneous detection of 5-fluorocytosine and 5-fluorouracil in human cells carrying CD/5-FC suicide gene system by using capillary zone electrophoresis.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1076:1-7, 2018 Feb 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A well-known suicide gene therapy approach, cytosine deaminase (CD) in combination with prodrug 5-flurocytosine (5-FC), has become an effective strategy of tumor treatment. However, there are short of simple and convenient detection methods to evaluate the efficiency of 5-FC conversion to 5-fluorouracil (5-FU) in human cells carrying various CD/5-FC systems. In this study, we developed an effective capillary zone electrophoresis (CZE) method to simultaneously measure 5-FC and 5-FU in cells carrying CD/5-FC suicide gene system. Under the condition of 60 mM borate buffer (pH 9.5) and 25 kV separation voltage with 0.5 psi × 15 s injection in 210 nm, the separation of 5-FC and 5-FU could be completely achieved within 15 min. The linearity of the calibration curve of standard 5-FC and 5-FU was in the range from 1 to 1000 µM (r > 0.999) and their recoveries were 98.4% and 96.0%, respectively. Due to the simple sample preparation and easy detection, this method is suitable for the study of the conversion efficiency of CD/5-FC suicide gene system. It aims to intuitively evaluate CD/5-FC systems and helps to guide the improvement of more effective CD/5-FC suicide gene systems.
[Mh] Termos MeSH primário: Eletroforese Capilar/métodos
Flucitosina/análise
Fluoruracila/análise
Genes Transgênicos Suicidas
[Mh] Termos MeSH secundário: Flucitosina/metabolismo
Fluoruracila/metabolismo
Células HEK293
Seres Humanos
Limite de Detecção
Modelos Lineares
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
D83282DT06 (Flucytosine); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:28748410
[Au] Autor:Komissarov A; Demidyuk I; Safina D; Roschina M; Shubin A; Lunina N; Karaseva M; Kostrov S
[Ad] Endereço:Laboratory of Protein Engineering, Institute of Molecular Genetics, Russian Academy of Science, 2 Kurchatova Sq., Moscow, Russia, 123182.
[Ti] Título:Cytotoxic effect of co-expression of human hepatitis A virus 3C protease and bifunctional suicide protein FCU1 genes in a bicistronic vector.
[So] Source:Mol Biol Rep;44(4):323-332, 2017 Aug.
[Is] ISSN:1573-4978
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recent reports on various cancer models demonstrate a great potential of cytosine deaminase/5-fluorocytosine suicide system in cancer therapy. However, this approach has limited success and its application to patients has not reached the desirable clinical significance. Accordingly, the improvement of this suicide system is an actively developing trend in gene therapy. The purpose of this study was to explore the cytotoxic effect observed after co-expression of hepatitis A virus 3C protease (3C) and yeast cytosine deaminase/uracil phosphoribosyltransferase fusion protein (FCU1) in a bicistronic vector. A set of mono- and bicistronic plasmid constructs was generated to provide individual or combined expression of 3C and FCU1. The constructs were introduced into HEK293 and HeLa cells, and target protein synthesis as well as the effect of 5-fluorocytosine on cell death and the time course of the cytotoxic effect was studied. The obtained vectors provide for the synthesis of target proteins in human cells. The expression of the genes in a bicistronic construct provide for the cytotoxic effect comparable to that observed after the expression of genes in monocistronic constructs. At the same time, co-expression of FCU1 and 3C recapitulated their cytotoxic effects. The combined effect of the killer and suicide genes was studied for the first time on human cells in vitro. The integration of different gene therapy systems inducing cell death (FCU1 and 3C genes) in a bicistronic construct allowed us to demonstrate that it does not interfere with the cytotoxic effect of each of them. A combination of cytotoxic genes in multicistronic vectors can be used to develop pluripotent gene therapy agents.
[Mh] Termos MeSH primário: Cisteína Endopeptidases/biossíntese
Citosina Desaminase/biossíntese
Flucitosina/farmacologia
Terapia Genética/métodos
Vírus da Hepatite A Humana/enzimologia
Pentosiltransferases/biossíntese
Proteínas Virais/biossíntese
[Mh] Termos MeSH secundário: Cisteína Endopeptidases/genética
Cisteína Endopeptidases/metabolismo
Citosina Desaminase/genética
Citosina Desaminase/metabolismo
Flucitosina/farmacocinética
Genes Transgênicos Suicidas
Vetores Genéticos
Células HEK293
Células HeLa
Vírus da Hepatite A Humana/metabolismo
Seres Humanos
Pentosiltransferases/genética
Pentosiltransferases/metabolismo
Plasmídeos/genética
Pró-Fármacos/farmacocinética
Pró-Fármacos/farmacologia
Transdução Genética
Proteínas Virais/genética
Proteínas Virais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Prodrugs); 0 (Viral Proteins); D83282DT06 (Flucytosine); EC 2.4.2.- (Pentosyltransferases); EC 2.4.2.9 (uracil phosphoribosyltransferase); EC 3.4.22.- (Cysteine Endopeptidases); EC 3.4.22.28 (3C proteases); EC 3.5.4.1 (Cytosine Deaminase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1007/s11033-017-4113-4


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[PMID]:28911170
[Au] Autor:Rebourcet D; Darbey A; Monteiro A; Soffientini U; Tsai YT; Handel I; Pitetti JL; Nef S; Smith LB; O'Shaughnessy PJ
[Ad] Endereço:Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom.
[Ti] Título:Sertoli Cell Number Defines and Predicts Germ and Leydig Cell Population Sizes in the Adult Mouse Testis.
[So] Source:Endocrinology;158(9):2955-2969, 2017 Sep 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sertoli cells regulate differentiation and development of the testis and are essential for maintaining adult testis function. To model the effects of dysregulating Sertoli cell number during development or aging, we have used acute diphtheria toxin-mediated cell ablation to reduce Sertoli cell population size. Results show that the size of the Sertoli cell population that forms during development determines the number of germ cells and Leydig cells that will be present in the adult testis. Similarly, the number of germ cells and Leydig cells that can be maintained in the adult depends directly on the size of the adult Sertoli cell population. Finally, we have used linear modeling to generate predictive models of testis cell composition during development and in the adult based on the size of the Sertoli cell population. This study shows that at all ages the size of the Sertoli cell population is predictive of resulting testicular cell composition. A reduction in Sertoli cell number/proliferation at any age will therefore lead to a proportional decrease in germ cell and Leydig cell numbers, with likely consequential effects on fertility and health.
[Mh] Termos MeSH primário: Células Germinativas/citologia
Células Intersticiais do Testículo/citologia
Células de Sertoli/citologia
Testículo/citologia
[Mh] Termos MeSH secundário: Envelhecimento/fisiologia
Animais
Contagem de Células
Diferenciação Celular
Toxina Diftérica/genética
Genes Transgênicos Suicidas
Células Germinativas/fisiologia
Crescimento e Desenvolvimento/fisiologia
Células Intersticiais do Testículo/fisiologia
Masculino
Camundongos
Camundongos Transgênicos
Fragmentos de Peptídeos/genética
Células de Sertoli/fisiologia
Maturidade Sexual/fisiologia
Espermatogênese/fisiologia
Espermatozoides/citologia
Espermatozoides/fisiologia
Testículo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diphtheria Toxin); 0 (Peptide Fragments); 0 (diphtheria toxin fragment A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00196


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[PMID]:28727740
[Au] Autor:Kalimuthu S; Oh JM; Gangadaran P; Zhu L; Lee HW; Jeon YH; Jeong SY; Lee SW; Lee J; Ahn BC
[Ad] Endereço:Department of Nuclear Medicine, Kyungpook National University School of Medicine/Hospital, Daegu, Republic of Korea.
[Ti] Título:Genetically engineered suicide gene in mesenchymal stem cells using a Tet-On system for anaplastic thyroid cancer.
[So] Source:PLoS One;12(7):e0181318, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene-based therapies. For example, use a synthetic "tetracycline-on" switch system to control the expression of the therapeutic gene thymidine kinase, which converts prodrugs to active drugs. The aim of this study was to develop therapeutic MSCs, harboring an inducible suicide gene, and to validate therapeutic gene expression using optical molecular imaging of ATC. We designed the Tet-On system using a retroviral vector expressing herpes simplex virus thymidine kinase (HSV1-sr39TK) with dual reporters (eGFP-Fluc2). Mouse bone marrow-derived mesenchymal stromal cells (BM-MSC) were transduced using this system with (MSC-Tet-TK/Fluc2) or without (MSC-TK/Fluc) the Tet-On system. Transduced cells were screened and characterized. Engineered MSCs were co-cultured with ATC (CAL62/Rluc) cells in the presence of the prodrug ganciclovir (GCV) and stimulated with DOX. The efficiency of cell killing monitored by assessing Rluc (CAL62/Rluc) and Fluc (MSC-Tet-TK/Fluc and MSC-TK/Fluc) activities using IVIS imaging. Fluc activity increased in MSC-Tet-TK/Fluc cells in a dose dependent manner following DOX treatment (R2 = 0.95), whereas no signal was observed in untreated cells. eGFP could also be visualized after induction with DOX, and the HSV1-TK protein could be detected by western blotting. In MSC-TK/Fluc cells, the Fluc activity increased with increasing cell number (R2 = 0.98), and eGFP could be visualized by fluorescence microscopy. The Fluc activity and cell viability of MSC-Tet-TK/Fluc and MSC-TK/Fluc cells decreased significantly following GCV treatment. A bystander effect of the therapeutic cells confirmed in co-cultures of CAL62 cells, an anaplastic thyroid cancer cell line, with either MSC-Tet-TK/Fluc cells or MSC-TK/Fluc cells. The Rluc activity in MSC-Tet-TK/Fluc co-cultures, derived from the CAL62/Rluc cells, decreased significantly with GCV treatment of DOX treated cultures, whereas no significant changes were observed in untreated cultures. In addition, the Fluc activity of MSC-Tet-TK/Fluc cells also decreased significantly with DOX treatment whereas no signal was present in untreated cultures. A bystander effect also be demonstrated in co-cultures with MSC-TK/Fluc cells and CAL62/Rluc; both the Rluc activity and the Fluc activity were significantly decreased following GCV treatment. We have successfully developed a Tet-On system of gene-directed enzyme/prodrug delivery using MSCs. We confirmed the therapeutic bystander effect in CAL62/Rluc cells with respect to MSC-Tet-TK/Fluc and MSC-TK/Fluc cells after GCV treatment with and without DOX. Our results confirm the therapeutic efficiency of a suicide gene, with or without the Tet-On system, for ATC therapy. In addition, our findings provide an innovative therapeutic approach for using the Tet-On system to eradicate tumors by simple, repeated administration of MSC-Tet-TK/Fluc cells with DOX and GCV.
[Mh] Termos MeSH primário: Genes Transgênicos Suicidas
Carcinoma Anaplásico da Tireoide/terapia
[Mh] Termos MeSH secundário: Animais
Engenharia Genética/métodos
Terapia Genética/métodos
Vetores Genéticos
Seres Humanos
Células Mesenquimais Estromais/fisiologia
Camundongos
Retroviridae
Tetraciclina/farmacologia
Carcinoma Anaplásico da Tireoide/genética
Carcinoma Anaplásico da Tireoide/patologia
Ativação Transcricional/efeitos dos fármacos
Transdução Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
F8VB5M810T (Tetracycline)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181318


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[PMID]:28393254
[Au] Autor:Wang X; Sun L; Sun X; Yu J; Wang K; Wu Y; Gao Q; Zheng J
[Ad] Endereço:Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
[Ti] Título:Antitumor effects of a dual-specific lentiviral vector carrying the Escherichia coli purine nucleoside phosphorylase gene.
[So] Source:Int J Oncol;50(5):1612-1622, 2017 May.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:The Escherichia coli purine nucleoside phosphorylase/Fludarabine phosphate (ePNP/Fludara) suicide system has several drawbacks, such as side-effects and the low efficiency of ePNP expression. In this study, we evaluated the antitumor effects of the dual-specific 8HSEs-hTERTp-ePNP/Fludara suicide system under hyperthermia in vitro and in vivo. Luciferase activities from the 8HSEs­hTERT and CMV promoters were compared using the dual luciferase assay in SW480 (high hTERT expression) and MKN74 cells (hTERT-negative) in the presence and absence of hyperthermia. Then, we investigated the effects of overexpressing the suicide gene ePNP using 8HSEs­hTERT-driven lentiviral vectors with Fludara on in vitro cell viability, side-effects, apoptosis, cycle distribution, colony formation and in vivo xenograft tumor growth. At 43ËšC, luciferase activity from the 8HSEs­hTERT promoter was significantly increased in SW480 cells, but not in MKN74 cells. Importantly, luciferase activities from the 8HSEs­hTERT promoter were much higher than from the CMV promoter in hTERT-expressing SW480 cells under heated conditions. The in vitro quantitative analysis showed a 4-fold higher ePNP protein expression from the 8HSEs­hTERT promoter at 43ËšC than at 37ËšC in SW480 cells and the ePNP mRNA expression in SW480 cells at 43ËšC was also higher than at 37ËšC. Conversely, ePNP mRNA and protein expression were low, almost absent, in hTERT-negative MKN74 cells with or without hyperthermia. After Fludara addition, cell cytotoxicity assays showed that the significant inhibitory effect of the 8HSEs­hTERTp-ePNP on SW480 cells was dose- and time-dependent with hyperthermia. The 8HSEs­hTERTp-ePNP/Fludara suicide system significantly inhibited SW480 cell viability, colony formation, cell cycle progression and induced apoptosis in vitro, but also induced significant bystander effects, especially under the heated conditions. At the protein level, the suicide system significantly promoted Bax, caspase-3 and p53 expression and suppressed Bcl-2 expression. In sections from mouse xenografts, TUNEL assays showed that the suicide system reduced xenograft growth and induced SW480 apoptosis. These results indicated that the combinatorial cancer- and heat-specific promoter system has great potential for improving the efficacy of cancer treatment with hyperthermia. The 8HSEs­hTERTp-ePNP/Fludara system may serve as a powerful strategy for cancer gene therapy combined with hyperthermia.
[Mh] Termos MeSH primário: Terapia Genética
Vetores Genéticos/uso terapêutico
Neoplasias/genética
Neoplasias/terapia
Purina-Núcleosídeo Fosforilase/genética
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Linhagem Celular Tumoral
Escherichia coli/genética
Regulação Enzimológica da Expressão Gênica
Genes Transgênicos Suicidas/genética
Vetores Genéticos/genética
Proteínas de Fluorescência Verde
Seres Humanos
Lentivirus/genética
Camundongos
Neoplasias/patologia
Purina-Núcleosídeo Fosforilase/biossíntese
Purina-Núcleosídeo Fosforilase/uso terapêutico
Telomerase/genética
Telomerase/uso terapêutico
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
147336-22-9 (Green Fluorescent Proteins); EC 2.4.2.1 (Purine-Nucleoside Phosphorylase); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2017.3949


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[PMID]:28301970
[Au] Autor:Bandeira VS; Tomás HA; Alici E; Carrondo MJ; Coroadinha AS
[Ad] Endereço:1 Instituto de Biologia Experimental e Tecnológica , Oeiras, Portugal .
[Ti] Título:Disclosing the Parameters Leading to High Productivity of Retroviral Producer Cells Lines: Evaluating Random Versus Targeted Integration.
[So] Source:Hum Gene Ther Methods;28(2):78-90, 2017 Apr.
[Is] ISSN:1946-6544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gammaretrovirus and lentivirus are the preferred viral vectors to genetically modify T and natural killer cells to be used in immune cell therapies. The transduction efficiency of hematopoietic and T cells is more efficient using gibbon ape leukemia virus (GaLV) pseudotyping. In this context gammaretroviral vector producer cells offer competitive higher titers than transient lentiviral vectors productions. The main aim of this work was to identify the key parameters governing GaLV-pseudotyped gammaretroviral vector productivity in stable producer cells, using a retroviral vector expression cassette enabling positive (facilitating cell enrichment) and negative cell selection (allowing cell elimination). The retroviral vector contains a thymidine kinase suicide gene fused with a ouabain-resistant Na ,K -ATPase gene, a potential safer and faster marker. The establishment of retroviral vector producer cells is traditionally performed by randomly integrating the retroviral vector expression cassette codifying the transgene. More recently, recombinase-mediated cassette exchange methodologies have been introduced to achieve targeted integration. Herein we compared random and targeted integration of the retroviral vector transgene construct. Two retroviral producer cell lines, 293 OuaS and 293 FlexOuaS, were generated by random and targeted integration, respectively, producing high titers (on the order of 10 infectious particles·ml ). Results showed that the retroviral vector transgene cassette is the key retroviral vector component determining the viral titers notwithstanding, single-copy integration is sufficient to provide high titers. The expression levels of the three retroviral constructs (gag-pol, GaLV env, and retroviral vector transgene) were analyzed. Although gag-pol and GaLV env gene expression levels should surpass a minimal threshold, we found that relatively modest expression levels of these two expression cassettes are required. Their levels of expression should not be maximized. We concluded, to establish a high producer retroviral vector cell line only the expression level of the genomic retroviral RNA, that is, the retroviral vector transgene cassette, should be maximized, both through (1) the optimization of its design (i.e., genetic elements composition) and (2) the selection of high expressing chromosomal locus for its integration. The use of methodologies identifying and promoting integration into high-expression loci, as targeted integration or high-throughput screening are in this perspective highly valuable.
[Mh] Termos MeSH primário: Terapia Genética
Vetores Genéticos/genética
Retroviridae/genética
Integração Viral/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Expressão Gênica
Genes Transgênicos Suicidas/genética
Vetores Genéticos/uso terapêutico
Seres Humanos
Lentivirus/genética
Vírus da Leucemia do Macaco Gibão/genética
ATPase Trocadora de Sódio-Potássio/genética
Timidina Quinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.21 (Thymidine Kinase); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1089/hgtb.2016.149


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[PMID]:28246701
[Au] Autor:Jeong HC; Cho SJ; Lee MO; Cha HJ
[Ad] Endereço:Dept. of Life Sciences, College of Natural Sciences, Sogang University, #1 Sinsu-dong, Mapo-gu, Seoul,, 121-742, Republic of Korea.
[Ti] Título:Technical approaches to induce selective cell death of pluripotent stem cells.
[So] Source:Cell Mol Life Sci;74(14):2601-2611, 2017 Jul.
[Is] ISSN:1420-9071
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Despite the recent promising results of clinical trials using human pluripotent stem cell (hPSC)-based cell therapies for age-related macular degeneration (AMD), the risk of teratoma formation resulting from residual undifferentiated hPSCs remains a serious and critical hurdle for broader clinical implementation. To mitigate the tumorigenic risk of hPSC-based cell therapy, a variety of approaches have been examined to ablate the undifferentiated hPSCs based on the unique molecular properties of hPSCs. In the present review, we offer a brief overview of recent attempts at selective elimination of undifferentiated hPSCs to decrease the risk of teratoma formation in hPSC-based cell therapy.
[Mh] Termos MeSH primário: Células-Tronco Pluripotentes/citologia
Transplante de Células-Tronco/métodos
[Mh] Termos MeSH secundário: Animais
Morte Celular/efeitos dos fármacos
Genes Transgênicos Suicidas
Seres Humanos
MicroRNAs/metabolismo
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Células-Tronco Pluripotentes/efeitos dos fármacos
Células-Tronco Pluripotentes/metabolismo
Bibliotecas de Moléculas Pequenas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (MicroRNAs); 0 (Small Molecule Libraries)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1007/s00018-017-2486-0


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[PMID]:28193196
[Au] Autor:Pahle J; Menzel L; Niesler N; Kobelt D; Aumann J; Rivera M; Walther W
[Ad] Endereço:Experimental and Clinical Research Center, Charité University Medicine, Lindenberger Weg 80, 13125, Berlin, Germany.
[Ti] Título:Rapid eradication of colon carcinoma by Clostridium perfringens Enterotoxin suicidal gene therapy.
[So] Source:BMC Cancer;17(1):129, 2017 Feb 13.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bacterial toxins have evolved to an effective therapeutic option for cancer therapy. The Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin with selective cytotoxicity. The transmembrane tight junction proteins claudin-3 and -4 are known high affinity CPE receptors. Their expression is highly upregulated in human cancers, including breast, ovarian and colon carcinoma. CPE binding to claudins triggers membrane pore complex formation, which leads to rapid cell death. Previous studies demonstrated the anti-tumoral effect of treatment with recombinant CPE-protein. Our approach aimed at evaluation of a selective and targeted cancer gene therapy of claudin-3- and/or claudin-4- expressing colon carcinoma in vitro and in vivo by using translation optimized CPE expressing vector. METHODS: In this study the recombinant CPE and a translation optimized CPE expressing vector (optCPE) was used for targeted gene therapy of claudin-3 and/or -4 overexpressing colon cancer cell lines. All experiments were performed in the human SW480, SW620, HCT116, CaCo-2 and HT-29 colon cancer and the isogenic Sk-Mel5 and Sk-Mel5 Cldn-3-YFP melanoma cell lines. Claudin expression analysis was done at protein and mRNA level, which was confirmed by immunohistochemistry. The CPE induced cytotoxicity was analyzed by the MTT cytotoxicity assay. In addition patient derived colon carcinoma xenografts (PDX) were characterized and used for the intratumoral in vivo gene transfer of the optCPE expressing vector in PDX bearing nude mice. RESULTS: Claudin-3 and -4 overexpressing colon carcinoma lines showed high sensitivity towards both recCPE application and optCPE gene transfer. The positive correlation between CPE cytotoxicity and level of claudin expression was demonstrated. Transfection of optCPE led to targeted, rapid cytotoxic effects such as membrane disruption and necrosis in claudin overexpressing cells. The intratumoral optCPE in vivo gene transfer led to tumor growth inhibition in colon carcinoma PDX bearing mice in association with massive necrosis due to the intratumoral optCPE expression. CONCLUSIONS: This novel approach demonstrates that optCPE gene transfer represents a promising and efficient therapeutic option for a targeted suicide gene therapy of claudin-3 and/or claudin-4 overexpressing colon carcinomas, leading to rapid and effective tumor cell killing in vitro and in vivo.
[Mh] Termos MeSH primário: Claudina-3/genética
Claudina-4/genética
Neoplasias do Colo/terapia
Enterotoxinas/uso terapêutico
Genes Transgênicos Suicidas
Terapia Genética
[Mh] Termos MeSH secundário: Animais
Efeito Espectador
Clostridium perfringens
Neoplasias do Colo/genética
Neoplasias do Colo/patologia
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CLDN3 protein, human); 0 (CLDN4 protein, human); 0 (Claudin-3); 0 (Claudin-4); 0 (Enterotoxins); 0 (enterotoxin, Clostridium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-017-3123-x


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[PMID]:28183639
[Au] Autor:Tirkey B; Bhushan B; Uday Kumar S; Gopinath P
[Ad] Endereço:Nanobiotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
[Ti] Título:Prodrug encapsulated albumin nanoparticles as an alternative approach to manifest anti-proliferative effects of suicide gene therapy.
[So] Source:Mater Sci Eng C Mater Biol Appl;73:507-515, 2017 Apr 01.
[Is] ISSN:1873-0191
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Conventional anticancer agents are associated with limited therapeutic efficacy and substantial nonspecific cytotoxicity. Thus, there is an imminent need for an alternative approach that can specifically annihilate the cancer cells with minimal side effects. Among such alternative approaches, CD::UPRT (cytosine deaminase uracil phosphoribosyl transferase) suicide gene therapy has tremendous potential due to its high efficacy. Prodrug 5-Fluorocytosine (5-FC) used in combination with CD::UPRT suicide gene suffers from limited solubility which subsequently leads to decline in therapeutic efficacy. In order to overcome this, 5-FC encapsulated bovine serum albumin nanoparticles (BSA-5-FC NPs) were prepared in this work by desolvation method. Physico-chemical characterizations studies revealed amorphous nature of BSA-5-FC NPs with uniform spherical morphology. Apart from increase in solubility, encapsulated 5-FC followed slow and sustained release profile. Suicide gene expressing stable clone of L-132 cells were adapted for investigating therapeutic potential of BSA-5-FC NPs. These nanoparticles were readily taken up by the cells in a concentration dependent manner and subsequently manifested apoptosis, which was further confirmed by morphological examination and gene expression analysis. These findings clearly illustrate that CD::UPRT suicide gene therapy can be efficiently utilized in combination with this nanosystem for improved suicide gene therapy and tumor eradication.
[Mh] Termos MeSH primário: Genes Transgênicos Suicidas
Terapia Genética
Nanopartículas/química
Pró-Fármacos/farmacologia
Soroalbumina Bovina/química
[Mh] Termos MeSH secundário: Animais
Bovinos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Liberação Controlada de Fármacos
Difusão Dinâmica da Luz
Endocitose/efeitos dos fármacos
Citometria de Fluxo
Flucitosina/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Nanopartículas/ultraestrutura
Espectroscopia de Infravermelho com Transformada de Fourier
Coloração e Rotulagem
Eletricidade Estática
Temperatura Ambiente
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Prodrugs); 27432CM55Q (Serum Albumin, Bovine); D83282DT06 (Flucytosine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE


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[PMID]:28035376
[Au] Autor:Konieczny P; Sulkowski M; Badyra B; Kijowski J; Majka M
[Ad] Endereço:Department of Transplantation, Faculty of Clinical Immunology and Transplantation, Jagiellonian University Medical College, 30-663 Krakow, Poland.
[Ti] Título:Suicide gene therapy of rhabdomyosarcoma.
[So] Source:Int J Oncol;50(2):597-605, 2017 Feb.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and young adulthood. Conventional treatment consisting of surgery, chemotherapy and radiotherapy can be insufficient, as long-term survival chances decrease dramatically when cancer recurrence occurs. Due to this fact, efficient treatment of this cancer is still a demanding issue, thus, novel and innovative therapies have to be considered as a part of combined treatment. In the present study, we present effective suicide gene therapy of rhabdomyosarcoma cell line Rh30 involving herpes simplex thymidine kinase (HSV-TK) and ganciclovir (GCV). Transduction of rhabdomyosarcoma cells using lentiviral vectors allowed efficient introduction of HSV-TK gene. In this study we proved high susceptibility of modified cells to ganciclovir resulting in eradication of cancer cells both in vitro and in vivo. Our data revealed strong gap junctional intercellular communication in examined cell line responsible for elimination of unmodified cells by bystander effect, even if HSV-TK-expressing cells comprise only 20% of cultured cells. Moreover, investigated approach is also efficient in vivo, where complete remission of tumors upon only 14 days of systemic administration of GCV can be observed. Obtained results suggest that HSV-TK suicide gene therapy is very promising concept in future clinical studies concerning rhabdomyosarcoma.
[Mh] Termos MeSH primário: Ganciclovir/administração & dosagem
Terapia Genética/métodos
Vetores Genéticos/administração & dosagem
Rabdomiossarcoma/terapia
Simplexvirus/enzimologia
Timidina Quinase/genética
[Mh] Termos MeSH secundário: Animais
Efeito Espectador/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Ganciclovir/farmacologia
Regulação Neoplásica da Expressão Gênica
Genes Transgênicos Suicidas
Seres Humanos
Camundongos
Rabdomiossarcoma/genética
Simplexvirus/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.21 (Thymidine Kinase); P9G3CKZ4P5 (Ganciclovir)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161231
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2016.3824



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