In VivoGene Therapy for Prostate Cancer: Preclinical Evaluation of Two Different Enzyme-Directed Prodrug Therapy Systems Delivered by Identical Adenovirus Vectors

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Abstract
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 ~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. By using recombinant adenovirus as a delivery vehicle, we have assessed two different enzyme-directed prodrug systems, HSVTK/GCV and PNP/6MPDR, under the control of the PSA promoter, for their ability to kill an AI prostate cancer cell line, PC-3, in vivo. Although PSA has been shown to be a weak promoter generally and is poorly expressed by PC-3 cells in vitro, we (Brookes et al., 1998) were able to achieve significant subcutaneous tumor regression following a single course of either EPT system in PC-3 cells grown in BALB/c nude mice. We are currently preparing new recombinant adenoviruses that have a stronger prostate-specific promoter. Gene therapy using such recombinant adenoviruses may be useful for treating patients with AI prostatic cancer.