A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer

• 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.

Nyckelord

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

MEDICINE

MEDICIN

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)