RESUMEN
More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.
Asunto(s)
Infecciones por Adenoviridae , Viroterapia Oncolítica , Virus Oncolíticos , Neoplasias Ováricas , Neoplasias del Cuello Uterino , Femenino , Humanos , Ratones , Animales , Adenoviridae/genética , Ascitis , Ratones Desnudos , Microambiente Tumoral , Línea Celular Tumoral , Neoplasias Ováricas/terapia , Neoplasias Ováricas/tratamiento farmacológico , Virus Oncolíticos/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Here we describe a collection of methods that have been adapted to isolate and modify tumor-specific promoters (TSPs ) to drive viral replication for cancer therapy and other uses. We will describe as examples the secreted protein acidic and rich in cysteine (SPARC ) and the protease-activated receptor-1 (PAR-1) promoter. We outline strategies to select appropriate TSPs using bioinformatics resources and the methods utilized in their subsequent cloning, assessment of transcriptional activity, and their use in conditionally replicative oncolytic adenoviruses .
Asunto(s)
Adenoviridae/fisiología , Viroterapia Oncolítica/métodos , Osteonectina/genética , Regiones Promotoras Genéticas , Receptor PAR-1/genética , Activación Transcripcional , Replicación Viral , Adenoviridae/genética , Animales , Clonación Molecular/métodos , Regulación Viral de la Expresión Génica , Vectores Genéticos/genética , Genómica/métodos , Humanos , Ratones , Neoplasias/genética , Neoplasias/terapia , Plásmidos/genética , RatasRESUMEN
Activity of endogenous promoters can be altered by including additional responsive elements (REs). These elements can be responsive to features of the tumor environment or alternatively to signaling pathways specifically activated in cancer cells. These REs incorporated into tumor-specific promoters can improve cancer targeting, the replicative capacity, and lytic activity of conditionally replicative adenovirus. Here we outline an approach to incorporate hypoxia and inflammation REs into a specific fragment of the SPARC promoter and the steps to clone a nucleosome positioning sequence (NPS ) identified in the osteocalcin promoter that contains a Wnt RE upstream of a heterologous synthetic promoter.
Asunto(s)
Adenoviridae/genética , Neoplasias/genética , Virus Oncolíticos/genética , Regiones Promotoras Genéticas , Microambiente Tumoral , Animales , Línea Celular Tumoral , Clonación Molecular/métodos , Regulación de la Expresión Génica , Células HEK293 , Humanos , Hipoxia/genética , Inflamación/genética , Neoplasias/metabolismo , Osteocalcina/genética , Plásmidos/genética , Ratas , Vía de Señalización WntRESUMEN
Marfan syndrome is the most common dominant autosomic genetic disorder of the connective tissue. It has areported incidence of 1 per each 5000 individuals without any distinction of gender or ethnicity. This pathologys diagnosis is mainly based on physical characteristics, presenting three main different symptomatic charts: neonatal Marfan, infant Marfan and classical Marfan. The mayor characteristic of these patients consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems and atypical bone overgrowth. The individual implied in the present investigation concerned to a 14 year old male patient presenting multiple mouth lesions and dental alterations, attended in the Department of Pediatric Dentistry degree at the Dentistry School in the Santa Maria University. The patient has been treated following the necessary considerations required according to his systemic compromised under oral premedication for decrease the anxiety and make easear the behavior management. The patirnt with MS has multiple oral decrease that maybe diagnoticated a treated on time to increase the life quality of the patient (AU)
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Asunto(s)
Humanos , Masculino , Adolescente , Síndrome de Marfan/complicaciones , Anomalías Dentarias/cirugía , Enfermedades Dentales/cirugía , Ansiedad al Tratamiento Odontológico/tratamiento farmacológico , Calidad de VidaRESUMEN
Marfan syndrome (MS) is the most common dominant autosomic genetic disorder of the connective tissue. It has a reported incidence of 1 per each 5000 individuals without any distinction of gender or ethnicity. This pathology's diagnosis is mainly based on physical characteristics, presenting three main different symptomatic charts: neonatal Marfan, infant Marfan and classical Marfan. The mayor characteristic of these patients consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems and atypical bone overgrowth. The individual implied in the present investigation concerned to a 14 year old male patient presenting multiple mouth lesions and dental alterations, attended in the Department of Pediatric Dentistry degree at the Dentistry School in the Santa Maria University. The patient has been treated following the necessary considerations required according to his systemic compromise under oral premedication for decrease the anxiety and make easier the behavior management. The patient with MS has multiple oral decrease that may be diagnosed as treated on time to increase the life quality of the patient.
Asunto(s)
Síndrome de Marfan/complicaciones , Enfermedades Dentales/etiología , Enfermedades Dentales/cirugía , Adolescente , Humanos , MasculinoRESUMEN
The possibility of inducing a strong immune response to impair tumor growth by ectopically expressing cytokines, followed by the generation of an antitumor memory raised great hopes and enthusiasm as a therapeutic approach. However, the efficacy of this strategy on established tumor models appeared low and the initial results in the clinics were disappointing. Recently, new evidence indicates that cytokine gene combination or the combined use of cytokine genes with additional gene therapy approaches induces a synergistic effect supporting the use of cytokine gene therapy to improve the clinical outcome for cancer patients.
Asunto(s)
Citocinas/inmunología , Terapia Genética , Memoria Inmunológica , Neoplasias/terapia , Animales , Citocinas/genética , Modelos Animales de Enfermedad , Humanos , Memoria Inmunológica/genética , Ratones , Neoplasias/genética , Neoplasias/inmunologíaRESUMEN
La terapia génica ofrece un tratamiento alternativo para el cáncer en el cual se utilizan vectores virales para facilitar la muerte de las células tumorales. Dado que un tumor está formado por células tumorales, fibroblastos y células endoteliales, el uso de adenovirus de replicación condicional (CRAds) que se puedan replicar en estos tres tipos celulares permitiría tratar a todos los responsables de la progresión tumoral. En este trabajo mostramos el desarrollo de un CRAd en el cual el promotor de SPARC se encuentra dirigiendo al gen viral E1A y la enzima herpetica timidina quinasa HSV-TK. Este vector adenoviral fue ensayado in vivo logrando la remisión del 50 por ciento de los tumores tratados
Asunto(s)
Adenovirus Humanos , Melanoma , BecasRESUMEN
La terapia génica ofrece un tratamiento alternativo para el cáncer en el cual se utilizan vectores virales para facilitar la muerte de las células tumorales. Dado que un tumor está formado por células tumorales, fibroblastos y células endoteliales, el uso de adenovirus de replicación condicional (CRAds) que se puedan replicar en estos tres tipos celulares permitiría tratar a todos los responsables de la progresión tumoral. En este trabajo mostramos el desarrollo de un CRAd en el cual el promotor de SPARC se encuentra dirigiendo al gen viral E1A y la enzima herpetica timidina quinasa HSV-TK. Este vector adenoviral fue ensayado in vivo logrando la remisión del 50 por ciento de los tumores tratados
Asunto(s)
Adenovirus Humanos , Melanoma , BecasRESUMEN
La terapia génica ofrece un tratamiento alternativo para el cáncer en el cual se utilizan vectores virales para facilitar la muerte de las células tumorales. Dado que un tumor está formado por células tumorales, fibroblastos y células endoteliales, el uso de adenovirus de replicación condicional (CRAds) que se puedan replicar en estos tres tipos celulares permitiría tratar a todos los responsables de la progresión tumoral. En este trabajo mostramos el desarrollo de un CRAd en el cual el promotor de SPARC se encuentra dirigiendo al gen viral E1A y la enzima herpetica timidina quinasa HSV-TK. Este vector adenoviral fue ensayado in vivo logrando la remisión del 50 por ciento de los tumores tratados