title: Targeting prostate cancer with conditionally replicative adenovirus using PSMA enhancer.
abstract: 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.
authors.affiliation: Department of Urology, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sang Don
authors.initials: SD
authors.lastname: Lee
authors.forename: Chaeyong
authors.initials: C
authors.lastname: Jung
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Hong-Sup
authors.initials: HS
authors.lastname: Kim
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Bae
authors.forename: Meei-Huey
authors.initials: MH
authors.lastname: Jeng
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
authors.forename: Thomas
authors.initials: T
authors.lastname: Gardner
mesh_terms: 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
chemical_list: D017500:Adenovirus E1A Proteins; D043425:Glutamate Carboxypeptidase II