An HSV-1 amplicon system for prostate-specific expression of ICP4 to complement oncolytic viral replication for in vitro and in vivo treatment of prostate cancer cells.
The aim of the present study was to determine whether a prostate-specific amplicon, containing a probasin-derived promoter (ARR(2)PB) upstream of an essential Herpes simplex virus-1 (HSV-1) viral gene, infected-cell polypeptide 4 (ICP4), could complement an HSV-1 helper virus with this gene deleted (ICP4-) and cause lytic replication specifically in prostate cancer cells. Two amplicon constructs, CMV-ICP4 and ARR(2)PB-ICP4, were packaged by a replication-deficient ICP4- helper virus. The amplicon viruses could complement ICP4- helper viruses to efficiently replicate and cause cell lysis in prostate cancer cells. Intratumoral injection of LNCaP human prostate cancer xenografts with either amplicon/helper virus resulted in >75% reduction in tumor volume and serum prostate specific antigen (PSA). Histological and Q-PCR (quantitative PCR) analyses indicated that the toxicity in nontumor tissues was much lower with ARR(2)PB-ICP4 than with CMV-ICP4 amplicon/helper virus. In conclusion, a replication-deficient HSV-1 virus could be complemented by an amplicon virus to restore its oncolytic activity in a tissue-specific and low toxicity fashion, illustrating that this approach could be a potentially useful strategy for developing an oncolytic viral therapy for prostate cancer.
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Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
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D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002522:Chlorocebus aethiops; D005784:Gene Amplification; D015316:Genetic Therapy; D006378:Helper Viruses / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*
D017874:Immediate-Early Proteins; D012367:RNA, Viral; C048925:herpes simplex virus, type 1 protein ICP4