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

Candelaria Gomez-Manzano, Cristina Balague, Ramon Alemany, Michael G. Lemoine, Paraskevi Mitlianga, Hong Jiang, Asadullah Khan, Marta Alonso, Frederick F. Lang, Charles A. Conrad, Ta Jen Liu, B. Nebiyou Bekele, W. K.Alfred Yung, Juan Fueyo

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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 × 108 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.

Original languageEnglish (US)
Pages (from-to)1821-1828
Number of pages8
JournalOncogene
Volume23
Issue number10
DOIs
StatePublished - Mar 11 2004

Keywords

  • Adenovirus
  • E1A
  • E1B
  • Glioma
  • Therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Gomez-Manzano, C., Balague, C., Alemany, R., Lemoine, M. G., Mitlianga, P., Jiang, H., Khan, A., Alonso, M., Lang, F. F., Conrad, C. A., Liu, T. J., Bekele, B. N., Yung, W. K. A., & Fueyo, J. (2004). A novel E1A-E1B mutant adenovirus induces glioma regression in vivo. Oncogene, 23(10), 1821-1828. https://doi.org/10.1038/sj.onc.1207321