In vivo gene therapy for prostate cancer: preclinical evaluation of two different enzyme-directed prodrug therapy systems delivered by identical adenovirus vectors.
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.
Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
R
R
Martiniello-Wilks
J
J
Garcia-Aragon
M M
MM
Daja
P
P
Russell
G W
GW
Both
P L
PL
Molloy
L J
LJ
Lockett
P J
PJ
Russell
D000230:Adenocarcinoma / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004926:Escherichia coli / Q000201:enzymology; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011355:Prodrugs / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000628:therapy*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D011683:Purine-Nucleoside Phosphorylase; D013937:Thymidine Kinase; D015774:Ganciclovir