title: Gene therapy for prostate cancer by controlling adenovirus E1a and E4 gene expression with PSES enhancer.
abstract: PSES is a chimeric enhancer containing enhancer elements from prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) genes that are prevalently expressed in androgen-independent prostate cancers. PSES shows strong activity equivalent to cytomegalovirus (CMV) promoter, specifically in PSA/PSMA-positive prostate cancer cells, the major cell types in prostate cancer in the absence of androgen. We developed a recombinant adenovirus (AdE4PSESE1a) by placing adenoviral E1a and E4 genes under the control of the bidirectional enhancer PSES and enhanced green fluorescent protein gene for the purpose of intratumoral virus tracking under the control of CMV promoter. Because of PSES being very weak in nonprostatic cells, including HEK293 and HER911 that are frequently used to produce recombinant adenovirus, AdE4PSESE1a can only be produced in the HER911E4 cell line which expresses both E1 and E4 genes. AdE4PSESE1a showed similar viral replication and tumor cell killing activities to wild-type adenovirus in PSA/PSMA-positive prostate cancer cells. The viral replication and tumor cell killing activities were dramatically attenuated in PSA/PSMA-negative cells. To test whether AdE4PSESE1a could be used to target prostate tumors in vivo, CWR22rv s.c. tumors were induced in nude mice and treated with AdE4PSESE1a via intratumoral and tail vein injection. Compared to tumors treated with control virus, the growth of CWR22rv tumors was dramatically inhibited by AdE4PSESE1a via tail vein injection or intratumoral injection. These data show that adenoviral replication can be tightly controlled in a novel fashion by controlling adenoviral E1a and E4 genes simultaneously with a single enhancer.
authors.affiliation: Departments of Urology, Microbiology and Immunology, Radiology, Medicine, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Hong-Sup
authors.initials: HS
authors.lastname: Kim
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Bae
authors.forename: Keith M
authors.initials: KM
authors.lastname: Stantz
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Chaeyong
authors.initials: C
authors.lastname: Jung
authors.forename: Juan A
authors.initials: JA
authors.lastname: Jiménez
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gardner
authors.forename: Meei-Huey
authors.initials: MH
authors.lastname: Jeng
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D017209:Apoptosis; D002478:Cells, Cultured; D004274:DNA, Recombinant; D004742:Enhancer Elements, Genetic; D015316:Genetic Therapy; D005822:Genetic Vectors; D043425:Glutamate Carboxypeptidase II / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D014162:Transfection; D014183:Transplantation, Heterologous; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D017504:Adenovirus E4 Proteins; D000954:Antigens, Surface; D004274:DNA, Recombinant; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen