title: Selective and augmented β-glucuronidase expression combined with DOX-GA3 application elicits the potent suppression of prostate cancer.
abstract: The present study was carried out to evaluate the specific and amplified β-glucuronidase (βG) expression in prostate cancer cells by using a prostate‑specific antigen (PSA) promoter-controlled bicistronic adenovirus and to evaluate the specific killing of prostate cancer cells after the application of the prodrug DOX‑GA3. Bicistronic adenoviral expression vectors were constructed, and the effectiveness of specific and amplified expression was evaluated using luciferase and EGFP as reporter genes. βG expression was detected in LNCaP cells after they were infected with the βG‑expressing PSA promoter-controlled bicistronic adenovirus. MTT assays were conducted to evaluate the cytoxicity on the infected cells after the application of the prodrug DOX‑GA3. Tumor growth inhibition was also evaluated in nude mice after treatment with the βG‑expressing adenovirus and DOX‑GA3. Selective and amplified expression was observed in the PSA-producing LNCaP cells, but not in the PSA‑non‑producing DU145 cells. Potent cytotoxity and a strong bystander effect were observed in the LNCaP cells after infection with the βG‑expressing adenovirus and the application of DOX‑GA3. Intravenous injection of a GAL4 regulated bicistronic adenovirus vector constructed to express βG under the control of the PSA promoter (Ad/PSAP‑GV16‑βG) and the application of DOX‑GA3 strongly inhibited tumor growth and prolonged the survival time of tumor‑bearing nude mice. Selective and amplified βG expression together with the prodrug DOX‑GA3 had an increased antitumor effect, showing great potential for prostate cancer therapy.
authors.affiliation: Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China.
authors.forename: Longxin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Qin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D005965:Glucuronates / Q000008:administration & dosage*; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D005965:Glucuronates; C407038:N-(4-doxorubicin-N-carbonyl(oxymethyl)phenyl)-O-glucuronyl carbamate; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D005966:Glucuronidase; D017430:Prostate-Specific Antigen