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Genetically modified adenoviruses against gliomas: from bench to bedside.

Abstract
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.
AuthorsCandelaria Gomez-Manzano, W K Alfred Yung, Ramon Alemany, Juan Fueyo
JournalNeurology (Neurology) Vol. 63 Issue 3 Pg. 418-26 (Aug 10 2004) ISSN: 1526-632X [Electronic] United States
PMID15304571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)
Chemical References
  • Adenovirus E1A Proteins
  • Adenovirus E1B Proteins
  • CLMP protein, human
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Oligopeptides
  • Receptors, Virus
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • arginyl-glycyl-aspartic acid
Topics
  • Adenovirus E1A Proteins (deficiency, genetics, physiology)
  • Adenovirus E1B Proteins (deficiency, genetics, physiology)
  • Adenoviruses, Human (genetics, physiology)
  • Apoptosis
  • Biological Therapy (methods)
  • Brain Neoplasms (drug therapy, genetics, metabolism, radiotherapy, therapy)
  • Cell Cycle
  • Combined Modality Therapy
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Cranial Irradiation
  • Cytopathogenic Effect, Viral
  • Defective Viruses (genetics, physiology)
  • Gene Expression Regulation, Viral
  • Genes, Viral (genetics)
  • Genetic Therapy
  • Glioma (drug therapy, genetics, metabolism, radiotherapy, therapy)
  • Models, Neurological
  • Oligopeptides (genetics)
  • Promoter Regions, Genetic (genetics)
  • Receptors, Virus (deficiency)
  • Retinoblastoma Protein (deficiency, physiology)
  • Species Specificity
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 (deficiency, physiology)
  • Virus Replication

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