In vivo gene therapy for prostate cancer: preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors

• Published in: Human gene therapy Vol. 9; no. 11; p. 1617
• Main Authors: Martiniello-Wilks, R, Garcia-Aragon, J, Daja, M M, Russell, P, Both, G W, Molloy, P L, Lockett, L J, Russell, P J
• Format: Journal Article
• Language: English
• Published: United States 20-07-1998
• Subjects: Adenocarcinoma - therapy; Adenoviridae - genetics; Animals; Escherichia coli - enzymology; Ganciclovir - pharmacology; Genetic Therapy; Genetic Vectors; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prodrugs - pharmacology; Prostatic Neoplasms - therapy; Purine-Nucleoside Phosphorylase - genetics; Purine-Nucleoside Phosphorylase - metabolism; Simplexvirus - enzymology; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Tumor Cells, Cultured
• ISSN: 1043-0342
• DOI: 10.1089/hum.1998.9.11-1617

Advanced prostate cancer is invariably lethal once it becomes androgen independent (AI). With the aim of developing a new treatment we have used the human androgen-independent prostate cancer cell line, PC-3, to evaluate the effectiveness of two enzyme-directed prodrug therapy (EPT) systems as a novel means for promoting tumor cell destruction in vivo. We have confined our study to the use of a PSA promoter, in a preliminary attempt to achieve prostate specificity. The two EPT systems used were the HSVTK/GCV and PNP/6MPDR systems. These were chosen for their differential dependence on DNA replication for their mechanism of action. In the present work, either the HSVTK or PNP gene, each controlled by a PSA promoter fragment, was delivered by an E1-, replication-deficient human adenovirus (Ad5) into PC-3 tumors growing subcutaneously in BALB/c nude mice. Tumors were injected with a single dose of recombinant Ad5 and mice were treated intraperitoneally with the appropriate prodrug, twice daily, for 6 days thereafter. The growth of established PC-3 tumors was significantly suppressed and host survival increased with a single course of HSVTK/GCV or PNP/6MPDR treatment. HSVTK/GCV-treated PC-3 tumor growth was 80% less than that of control treatments on day 33, while PNP/6MPDR-treated tumor growth was approximately 75% less than that of control treatments on day 52. Survival data showed that 20% of HSVTK/GCV- or PNP/6MPDR-treated animals lived >45 and >448 days, respectively, longer than control animals. These results demonstrate that both HSVTK/GCV and PNP/6MPDR therapies interrupt the growth of an aggressive human prostate cancer cell line in vivo.