uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Show others and affiliations
2004 (English)In: Molecular Therapy, ISSN 1525-0016, Vol. 10, no 2, 355-364 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
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
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92861DOI: 10.1016/j.ymthe.2004.05.022PubMedID: 15294182OAI: oai:DiVA.org:uu-92861DiVA: diva2:166167
Available from: 2005-04-11 Created: 2005-04-11 Last updated: 2010-02-05Bibliographically approved
In thesis
1. TARP Promoter-Based Prostate Cancer Gene Therapy: From Development to Application
Open this publication in new window or tab >>TARP Promoter-Based Prostate Cancer Gene Therapy: From Development to Application
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is one leading cause of cancer-related death among men in Western countries. The standard therapies for localized prostate cancer include radical prostatectomy and radiation therapy. Such measures are relatively effective in the short term, but many patients ultimately relapse. These patients may benefit from a combination of standard therapy and oncolytic virus therapy. My work aimed to develop viruses for this purpose.

TARP is a protein that in males is specifically expressed in prostate epithelial and cancer cells. In my thesis, I characterized the TARP promoter and showed that TARP expression is regulated at the transcriptional level by testosterone through binding of the androgen receptor in the proximal TARP promoter. I further developed TARP promoter-based regulatory sequences for prostate-specific gene expression. A sequence comprising a PSA enhancer, a PSMA enhancer and the TARP promoter was constructed and designated PPT. An adenoviral vector containing the PPT sequence shielded from transcriptional interference by an H19 insulator showed high prostate-specific transcriptional activity in human cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer the PPT sequence is not active. Therefore, a two-step transcriptional amplification (TSTA) system was used together with the PPT sequence to develop an adenovirus that confers prostate-specific transgene expression also in murine cells.

I constructed a conditionally replicating adenovirus where the E1A gene expression is controlled by an H19 insulator-shielded PPT regulatory sequence, Ad[I/PPT-E1A]. This virus exhibited absolute prostate specificity in terms of E1A expression, viral replication and cytolysis in vitro and in vivo. Importantly, our virus is active both in the presence and absence of testosterone, which may prove beneficial for patients treated by hormonal withdrawal.

Hopefully, my work will improve existing gene therapy strategies for prostate cancer and in the long term improve the prognosis for patients with prostate cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 24
Genetic engineering, TARP, PPT, TSTA, promoter, gene regulation, prostate specificity, hormone- independent, adenovirus, prostate cancer, gene therapy, conditionally replicating adenovirus, Genteknik
National Category
Other Industrial Biotechnology
urn:nbn:se:uu:diva-5736 (URN)91-554-6205-7 (ISBN)
Public defence
2005-05-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15
Available from: 2005-04-11 Created: 2005-04-11Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Nilsson, BerithTötterman, Thomas H.Essand, Magnus
By organisation
Clinical ImmunologyDepartment of Oncology, Radiology and Clinical Immunology
In the same journal
Molecular Therapy
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 272 hits
ReferencesLink to record
Permanent link

Direct link