Oncolytic herpes virus with defective ICP6 specifically replicates in quiescent cells with homozygous genetic mutations in p16
| Autor: | Manish K. Aghi, E A Chiocca, Ronald A. DePinho, T Visted |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
viruses p16 medicine.disease_cause Virus Replication Oncolytic herpes virus Mice 0302 clinical medicine glioma Tumor Virus 2.1 Biological and endogenous factors Simplexvirus Aetiology Cells Cultured Cancer Mice Knockout Oncolytic Virotherapy 0303 health sciences Cultured Brain Neoplasms Cell Cycle Homozygote Glioma Cell cycle gene therapy 3. Good health Oncolytic Viruses 030220 oncology & carcinogenesis Infection mechanism of replication brain tumor Tumor suppressor gene Cells Knockout Clinical Sciences Oncology and Carcinogenesis Biology Article Virus 03 medical and health sciences Viral Proteins Rare Diseases tumor-suppressor gene Genetics medicine Animals Humans Oncology & Carcinogenesis Molecular Biology 030304 developmental biology oncolytic virus Genes p16 Virology Brain Disorders Oncolytic virus Brain Cancer Viral replication Genes Mutation Sexually Transmitted Infections Carcinogenesis |
| Zdroj: | Oncogene, vol 27, iss 30 Oncogene |
| Popis: | Oncolytic herpes simplex viruses (HSVs), in clinical trials for the treatment of malignant gliomas, are assumed to be selective for tumor cells because their replication is strongly attenuated in quiescent cells, but not in cycling cells. Oncolytic selectivity is thought to occur because mutations in viral ICP6 (encoding a viral ribonucleotide reductase function) and/or gamma34.5 function are respectively complemented by mammalian ribonucleotide reductase and GADD34, whose genes are expressed in cycling cells. However, it is estimated that only 5-15% of malignant glioma cells are in mitosis at any one time. Therefore, effective replication of HSV oncolytic viruses might be limited to a subpopulation of tumor cells, since at any one time the majority of tumor cells would not be cycling. However, we report that an HSV with defective ICP6 function replicates in quiescent cultured murine embryonic fibroblasts obtained from mice with homozygous p16 deletions. Furthermore, intracranial inoculation of this virus into the brains of p16-/- mice provides evidence of viral replication that does not occur when the virus is injected into the brains of wild-type mice. These approaches provide in vitro and in vivo evidence that ICP6-negative HSVs are 'molecularly targeted,' because they replicate in quiescent tumor cells carrying specific oncogene deletions, independent of cell cycle status. |
| Databáze: | OpenAIRE |
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