Selective and augmented β-glucuronidase expression combined with DOX-GA3 application elicits the potent suppression of prostate cancer.

The present study was carried out to evaluate the specific and amplified beta-glucuronidase (beta G) 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. beta G expression was detected in LNCaP cells after they were infected with the beta G-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 beta G-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 beta G-expressing adenovirus and the application of DOX-GA3. Intravenous injection of a GAL4 regulated bicistronic adenovirus vector constructed to express beta G under the control of the PSA promoter (Ad/PSAP-GV16-beta G) and the application of DOX-GA3 strongly inhibited tumor growth and prolonged the survival time of tumor-bearing nude mice. Selective and amplified beta G expression together with the prodrug DOX-GA3 had an increased antitumor effect, showing great potential for prostate cancer therapy.