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 475% 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 ARR2PB-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.