Transcriptional and Translational Dual-regulated Oncolytic Herpes Simplex Virus Type 1 for Targeting Prostate Tumors
| Autor: | Paul S. Rennie, William Jia, Cleo Y F Lee, Arrigo DeBenedetti, Luke X X Bu, B. Jill Williams |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
viruses Blotting Western Mice Nude Herpesvirus 1 Human Biology medicine.disease_cause Virus Mice Cell Line Tumor Drug Discovery Translational regulation LNCaP Genetics medicine Animals Humans Molecular Biology Pharmacology Oncolytic Virotherapy Reverse Transcriptase Polymerase Chain Reaction Prostatic Neoplasms Original Articles Molecular biology Xenograft Model Antitumor Assays Oncolytic virus Herpes simplex virus Viral replication Lytic cycle Cell culture Molecular Medicine |
| Popis: | The aim of this project was to demonstrate that an oncolytic herpes simplex virus type 1 (HSV-1) can replicate in a tissue- and tumor-specific fashion through both transcriptional (prostate-specific promoter, ARR(2)PB) and translational (5'-untranslated regions (5'UTRs) of rFGF-2) regulation of an essential viral gene, ICP27. We generated two recombinant viruses, ARR(2)PB-ICP27 (A27) and ARR(2)PB-5'UTR-ICP27 (AU27) and tested their efficacy and toxicity both in vitro and in vivo. The ARR(2)PB promoter caused overexpression of ICP27 gene in the presence of activated androgen receptors (ARs) and increased viral replication in prostate cells. However, this transcriptional upregulation was effectively constrained by the 5'UTR-mediated translational regulation. Mice bearing human prostate LNCaP tumors, treated with a single intravenous injection of 5 x 10(7) plaque-forming units (pfu) of AU27 virus exhibited a85% reduction in tumor size at day 28 after viral injection. Although active viral replication was readily evident in the tumors, no viral DNA was detectable in normal organs as measured by real-time PCR analyses. In conclusion, a transcriptional and translational dual-regulated (TTDR) viral essential gene expression can increase both viral lytic activity and tumor specificity, and this provides a basis for the development of a novel tumor-specific oncolytic virus for systemic treatment of locally advanced and metastatic prostate cancers. |
| Databáze: | OpenAIRE |
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