Anti-tumor activity of a miR-199-dependent oncolytic adenovirus.

Anti-tumor activity of a miR-199-dependent oncolytic adenovirus.

The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specifi...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Elisa Callegari, Bahaeldin K Elamin, Lucilla D'Abundo, Simonetta Falzoni, Giovanna Donvito, Farzaneh Moshiri, Maddalena Milazzo, Giuseppe Altavilla, Luciano Giacomelli, Francesca Fornari, Akseli Hemminki, Francesco Di Virgilio, Laura Gramantieri, Massimo Negrini, Silvia Sabbioni
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2013
Materias:
Medicine
R
Science
Q
Acceso en línea:https://doaj.org/article/e32ca045d1634705983595653fa456a4
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario:The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3' UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity.

Ejemplares similares