Targeting gene therapy for prostate cancer using prostate specific antigen (PSA)

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As a new treatment of prostate cancer, we are investigating a gene therapy model that utilizes a suicide gene cytosine deaminase (CD) that metabolizes non-toxic 5-fluorocytosine (5-FC) into toxic 5-fluorouracil (5-FU) in a LNCaP human prostate cancer model. The vector pC/CD was used to transfect LNCaP cells. 5 -FC showed a significantly lower ID50 value against the clones LN/CD than the control cells transfected with an empty vector, which was sensitive to 5-FU.Tumors made with LN/CD inoculation in nude mice were shown to regress after i.p.administration of 5-FC.The expression of the CD gene was effective in therapy of the LNCaP prostate cancer model both in vitro and in vivo. We used regulatory elements from the PSMA gene to develop a construct that could be used to control expression of a CD gene in a gene therapy approach against this disease. We recently cloned the promoter of the PSMA gene, which can drive prostate-specific expression of a luciferase reporter gene.NF κ B inhibitors, pyrrolidine dithiocarbamate (PDTC) and NF κ B decoy, continuously inhibited TNF-α-induced NF κ B activation. Prostate cancer cells treated with TNF-α (20 ng/ml) plus NF κ B inhibitors showed significant growth inhibition. The combination of TNF-α and NF κ B inhibitors was suggested to be an effective therapy for prostate cancer.We evaluate the antitumoral effect of a conditionally-replicating herpes simplex virus 1 (HSV-1) vector, G207, against prostate cancer in vitro and in vivo. DU145 and PC3 were efficiently destroyed by G207 within 7 days. The viral yields of G207 increased time-dependently. In vivo, the intraneoplastic inoculation of G207 induced a significant inhibition of the tumor growth. In a pathological study, a large number of lacZ positive cells were diffusely present in the G207-treated tumors. G207 thus may be considered a useful agent for the treatment of prostate cancer.