Details

Autor(en) / Beteiligte

• GOMEZ-MANZANO, Candelaria
• BALAGUE, Cristina
• LIU, Ta-Jen
• NEBIYOU BEKELE, B
• YUNG, W. K
• FUEYO, Juan
• ALEMANY, Ramon
• LEMOINE, Michael G
• MITLIANGA, Paraskevi
• HONG JIANG
• KHAN, Asadullah
• ALONSO, Marta
• LANG, Frederick F
• CONRAD, Charles A

Titel

A novel E1A-E1B mutant adenovirus induces glioma regression in vivo

Ist Teil von

• Oncogene, 2004-03, Vol.23 (10), p.1821-1828

Ort / Verlag

Basingstoke: Nature Publishing

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• Malignant gliomas are the most frequently occurring primary brain tumors and are resistant to conventional therapy. Conditionally replicating adenoviruses are a novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses have been reported recently and E1A mutant replication-competent adenoviruses are in advanced preclinical testing. Here we constructed a novel replication-selective adenovirus (CB1) incorporating a double deletion of a 24 bp Rb-binding region in the E1a gene, and a 903 bp deleted region in the E1b gene that abrogates the expression of a p53-binding E1B-55 kDa protein. CB1 exerted a potent anticancer effect in vitro in U-251 MG, U-373 MG, and D-54 MG human glioma cell lines, as assessed by qualitative and quantitative viability assays. Replication analyses demonstrated that CB1 replicates in vitro in human glioma cells. Importantly, CB1 acquired a highly attenuated replicative phenotype in both serum-starved and proliferating normal human astrocytes. In vivo experiments using intracranially implanted D-54 MG glioma xenografts in nude mice showed that a single dose of CB1 (1.5 x 10(8) PFU/tumor) significantly improved survival. Immunohistochemical analyses of expressed adenoviral proteins confirmed adenoviral replication within the tumors. The CB1 oncolytic adenovirus induces a potent antiglioma effect and could ultimately demonstrate clinical relevance and therapeutic utility.