Tightly-regulated suicide gene expression kills PSA-expressing prostate tumor cells.
We have previously shown that a dual system for controlling gene expression that relies both on transcriptional regulation and DNA recombination mediated by the site-directed recombinase, Flp, effectively controls the expression of a gene encoding diphtheria toxin (DT-A). In this study, we investigated the use of a chimeric modified enhancer/promoter sequence of the human prostate-specific antigen (PSA) gene to regulate DT-A expression in human prostate cancer cells in culture, in xenografts derived from these cells, and in autochthonous tumors in TRAMP mice. Following adenoviral delivery of DNA encoding PSA promoter-driven Flp recombinase and DT-A, we demonstrate that this transcriptional/DNA recombination control strategy effectively activates DT-A expression in a manner that correlates with the amount of PSA and androgen in cells. Significantly, the size of xenografts was reduced by 50%, and tumor cells in TRAMP mice died following intratumoral injection of DT-A viruses. Direct injection of virally-delivered DT-A into normal mouse prostates resulted in a dramatic reduction in the size of the gland. Our results suggest that the PSA promoter-driven Flp recombinase regulatory system will allow for targeted death of PSA-expressing cells. When combined with newly developed strategies for targeted gene delivery, this approach holds promise as an effective systemically-administered therapy for metastatic prostate cancer.
Peng
W
W
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
Chen
J
J
Huang
Y-H
YH
Sawicki
J A
JA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004254:DNA Nucleotidyltransferases / Q000235:genetics* / Q000378:metabolism; D004167:Diphtheria Toxin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D004167:Diphtheria Toxin; D010446:Peptide Fragments; C029795:diphtheria toxin fragment A; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase; D017430:Prostate-Specific Antigen