title: An efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy of human hepatocellular carcinomas.
abstract: Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.
authors.affiliation: Laboratory of Cancer Gene Therapy, Division of Cellular and Molecular Research, National Cancer Centre, Singapore. cmrlyp@nccs.com.sg
authors.forename: Paula Y P
authors.initials: PY
authors.lastname: Lam
authors.forename: Kian Chuan
authors.initials: KC
authors.lastname: Sia
authors.forename: Jenn H
authors.initials: JH
authors.lastname: Khong
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.forename: Kar S
authors.initials: KS
authors.lastname: Lim
authors.forename: Ivy A W
authors.initials: IA
authors.lastname: Ho
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Wang
authors.forename: L V
authors.initials: LV
authors.lastname: Miao
authors.forename: H
authors.initials: H
authors.lastname: Huynh
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D023081:CCAAT-Binding Factor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000515:alpha 1-Antitrypsin / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D023081:CCAAT-Binding Factor; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin; D000509:alpha-Fetoproteins; D008156:Luciferases