Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter.
Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.
Ahn
M
M
Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Lee
S-J
SJ
Li
X
X
Jiménez
J A
JA
Zhang
Y-P
YP
Bae
K-H
KH
Mohammadi
Y
Y
Kao
C
C
Gardner
T A
TA
D000256:Adenoviridae; D000818:Animals; D045744:Cell Line, Tumor; D041722:Genes, Transgenic, Suicide; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
D014764:Viral Proteins; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen
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