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Two-step transcriptional amplification (TSTA) of the PPT regulatory sequence in murine and human prostate cancer cell lines
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-92863OAI: oai:DiVA.org:uu-92863DiVA: diva2:166169
Available from: 2005-04-11 Created: 2005-04-11 Last updated: 2010-01-13Bibliographically 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

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