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

Oncogene volume 23, pages 1821–1828 (2004)Cite this article

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.

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Acknowledgements

We thank Joann Aaron for editorial assistance (Department of Neuro-Oncology, MD Anderson Cancer Center). This work was supported by the Pediatric Brain Tumor Foundation of the United States, The University of Texas MD Anderson Cancer Center, the Anthony Bullock Foundation and the National Institutes of Health R01CA90879.

Author information

Author notes

  1. Cristina Balague

    Present address: Target Validation Unit, Almirall Prodesfarma, Barcelona, 08028, Spain

Authors and Affiliations

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Box 316, 1515 Holcombe Blvd., Houston, 77030, TX, USA

    Candelaria Gomez-Manzano, Michael G Lemoine, Paraskevi Mitlianga, Hong Jiang, Marta Alonso, Charles A Conrad, Ta-Jen Liu, WK Alfred Yung & Juan Fueyo

  2. Gene Therapy Center, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Cristina Balague

  3. Institut Catala d'Oncologia, Barcelona, 08907, Spain

    Ramon Alemany

  4. Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Asadullah Khan

  5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Frederick F Lang

  6. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    B Nebiyou Bekele

Authors
  1. Candelaria Gomez-Manzano
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  2. Cristina Balague
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  3. Ramon Alemany
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  4. Michael G Lemoine
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  7. Asadullah Khan
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  8. Marta Alonso
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  9. Frederick F Lang
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  10. Charles A Conrad
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  11. Ta-Jen Liu
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  13. WK Alfred Yung
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  14. Juan Fueyo
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Corresponding author

Correspondence to Juan Fueyo.

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Gomez-Manzano, C., Balague, C., Alemany, R. et al. A novel E1A–E1B mutant adenovirus induces glioma regression in vivo. Oncogene 23, 1821–1828 (2004). https://doi.org/10.1038/sj.onc.1207321

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