A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer
2004 (English)In: Molecular Therapy, ISSN 1525-0016, Vol. 10, no 2, 355-364 p.Article in journal (Refereed) Published
TARP (T cell receptor gamma-chain alternate reading frame protein) is a protein that in males is uniquely expressed in prostate epithelial cells and prostate cancer cells. We have previously shown that the transcriptional activity of a chimeric sequence comprising the TARP promoter (TARPp) and the PSA enhancer (PSAe) is strictly controlled by testosterone and highly restricted to cells of prostate origin. Here we report that a chimeric sequence comprising TARPp and the PSMA enhancer (PSMAe) is highly active in testosterone-deprived prostate cancer cells, while a regulatory sequence comprising PSAe, PSMAe, and TARPp (PPT) has high prostate-specific activity both in the presence and in the absence of testosterone. Therefore, the PPT sequence may, in a gene therapy setting, be beneficial to prostate cancer patients that have been treated with androgen withdrawal. A recombinant adenovirus vector with the PPT sequence, shielded from interfering adenoviral sequences by the mouse H19 insulator, yields high and prostate-specific transgene expression both in cell cultures and when prostate cancer, PC-346C, tumors were grown orthotopically in nude mice. Intravenous virus administration reveals both higher activity and higher selectivity for the insulator-shielded PPT sequence than for the immediate-early CMV promoter. Therefore, we believe that an adenovirus with therapeutic gene expression controlled by an insulator-shielded PPT sequence is a promising candidate for gene therapy of prostate cancer.
Place, publisher, year, edition, pages
2004. Vol. 10, no 2, 355-364 p.
Adenoviridae/*genetics, Animals, Cell Line; Tumor, Enhancer Elements (Genetics)/genetics, Gene Expression Regulation; Neoplastic, Gene Therapy/*methods, Genes; Reporter/genetics, Genetic Vectors/genetics, Humans, Insulator Elements/genetics, Luciferases/analysis/genetics, Male, Mice, Neoplasms; Hormone-Dependent/genetics/*metabolism/therapy, Nuclear Proteins/*genetics, Promoter Regions (Genetics)/*genetics, Prostatic Neoplasms/genetics/*metabolism/therapy, Research Support; Non-U.S. Gov't, Testosterone/metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-92861DOI: 10.1016/j.ymthe.2004.05.022PubMedID: 15294182OAI: oai:DiVA.org:uu-92861DiVA: diva2:166167