Targeting prostate cancer with conditionally replicative adenovirus using PSMA enhancer.
Prostate cancer is the second most commonly diagnosed cancer in men and accounts for significant mortality and morbidity in the United States. Initially androgen-dependent, prostate cancer ultimately becomes androgen-independent, which makes the disease extremely difficult to cure. In this study, we examined the use of conditionally replication-competent adenovirus for the treatment of hormone-independent prostate cancer. We utilized PSME, an enhancer element for prostate-specific PSMA expression, to control viral E1A protein expression and achieve exclusive virus replication in prostate. Western blotting confirmed that PSME mediated high E1A protein expression in PSMA-positive, androgen-independent prostate cancer cells (C4-2 and CWR22rv), but was much less active in PSMA-negative cancer cells (PC-3 and A549). Consistent with E1A protein expression, the recombinant adenovirus Ad5-PSME-E1a replicated in C4-2 and CWR22rv almost as efficiently as wild type with low levels of androgen, but its replication was significantly attenuated in PSMA-negative cells. In the in vitro killing assay, Ad5-PSME-E1a lysed all C4-2 and CWR22rv cells 5 days after infection, with minimal effect on PSMA-negative cells. In addition, injections of 1.7 x 10(8) plaque-forming units in a CWR22rv xenograft model in nude mice induced significant tumor growth delay, with a substantial necrotic area. These studies suggest that PSME-driven replication-competent adenovirus may be a new therapeutic modality for prostate cancer patients after hormone ablation therapy.
Lee
Sang-Jin
SJ
Department of Urology, Indiana University, Indianapolis, IN 46202, USA.
Zhang
Yanping
Y
Lee
Sang Don
SD
Jung
Chaeyong
C
Li
Xiong
X
Kim
Hong-Sup
HS
Bae
Kyung-Hee
KH
Jeng
Meei-Huey
MH
Kao
Chinghai
C
Gardner
Thomas
T
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D043425:Glutamate Carboxypeptidase II / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014158:Transcription, Genetic / Q000235:genetics; D014771:Virion / Q000378:metabolism; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D043425:Glutamate Carboxypeptidase II