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Genetically modified adenoviruses against gliomas

From bench to bedside

From the Department of Neuro-Oncology (Drs. Gomez-Manzano, Yung, and Fueyo), The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Institut Catala d’Oncologia (Dr. Alemany), Barcelona, Spain.

Address correspondence and reprint requests to Dr. Juan Fueyo, Department of Neuro-Oncology, Box 316, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX; e-mail: jfueyo{at}mdanderson.org

Oncolytic or tumor-selective adenoviruses are constructed as novel antiglioma therapies. After infection, the invading genetic adenoviral material is activated within the host cell. E1A and E1B adenoviral proteins are expressed immediately. E1A protein interacts with cell cycle regulatory proteins, such as retinoblastoma (Rb), driving the cell into the S phase and ensuing viral replication. The action of E1A stimulates the cellular p53 tumor suppressor system, which results in growth arrest or apoptosis, and halts adenovirus replication. However, adenoviral E1B interacts with p53 protein, preventing the DNA replication process from being abrogated by the induction of p53-mediated apoptosis. It was subsequently hypothesized that mutant adenoviruses that were unable to express wild-type E1A or E1B proteins could not replicate in normal cells with functional Rb or p53 pathways but instead would replicate and kill glioma cells that had defects in the regulation of these tumor suppressor pathways. Mutant E1B adenoviruses have already entered the clinical setting as an experimental treatment for patients with malignant gliomas. Mutant E1A adenoviruses are now in preclinical development as antiglioma therapy. In this review, the authors describe the mechanisms underlying the production of oncolytic adenoviruses, preclinical and clinical experiences with specific oncolytic adenoviruses, and the possibilities of combining mutant oncolytic adenoviruses with gene therapy or conventional therapies for managing malignant gliomas.

Received August 18, 2003. Accepted in final form March 8, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the August 10 issue to find the title link for this article.

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