Gene therapy for prostate cancer by controlling adenovirus E1a and E4 gene expression with PSES enhancer.
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.
Li
Xiong
X
Departments of Urology, Microbiology and Immunology, Radiology, Medicine, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana.
Zhang
Yan-Ping
YP
Kim
Hong-Sup
HS
Bae
Kyung-Hee
KH
Stantz
Keith M
KM
Lee
Sang-Jin
SJ
Jung
Chaeyong
C
Jiménez
Juan A
JA
Gardner
Thomas A
TA
Jeng
Meei-Huey
MH
Kao
Chinghai
C
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
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