Transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 for targeting prostate tumors.
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 a >85% 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.
Lee
Cleo Y F
CY
The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
Bu
Luke X X
LX
DeBenedetti
Arrigo
A
Williams
B Jill
BJ
Rennie
Paul S
PS
Jia
William W G
WW
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays