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

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Show others and affiliations
2006 (English)In: Cancer Gene Therapy, ISSN 0929-1903, Vol. 13, no 1, 13-20 p.Article in journal (Refereed) Published
Abstract [en]

The use of conditionally replicating adenoviruses offers an attractive complementary treatment strategy for localized prostate cancer. We have produced a replicating adenovirus, Ad[I/PPT-E1A], where E1A gene expression is controlled by a recombinant regulatory sequence designated PPT. The PPT sequence comprises a PSA enhancer, a PSMA enhancer and a T-cell receptor gamma-chain alternate reading frame protein promoter, and it is shielded from transcriptional interference from adenoviral backbone sequences by an H19 insulator. Ad[I/PPT-E1A] yields prostate-specific E1A protein expression, viral replication and cytolysis in vitro. Furthermore, Ad[I/PPT-E1A] considerably regresses the growth of subcutaneous LNCaP prostate cancer tumors in nude mice. Importantly, the viral replication and cytolytic effect of Ad[I/PPT-E1A] are independent of the testosterone levels in the prostate cancer cells. This may be beneficial in a clinical setting since many prostate cancer patients are treated with androgen withdrawal. In conclusion, Ad[I/PPT-E1A] may prove to be useful in the treatment of localized prostate cancer.

Place, publisher, year, edition, pages
2006. Vol. 13, no 1, 13-20 p.
Keyword [en]
Adenoviridae/*metabolism, Adenovirus E1A Proteins/genetics/metabolism, Animals, Gene Expression Regulation; Neoplastic, Genetic Vectors/metabolism/therapeutic use, Humans, Male, Mice, Mice; Inbred C57BL, Mice; Nude, Neoplasms; Hormone-Dependent/genetics/*metabolism, Prostatic Neoplasms/*metabolism, Testosterone/metabolism, Time Factors, Transfection, Virus Replication
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-92862DOI: 10.1038/sj.cgt.7700881.PubMedID: 16052227OAI: oai:DiVA.org:uu-92862DiVA: diva2:166168
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 24
Keyword
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
Identifiers
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
Opponent
Supervisors
Available from: 2005-04-11 Created: 2005-04-11Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Dzojic, HelenaNilsson, BerithTötterman, Thomas H.Essand, Magnus

Search in DiVA

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

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 749 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf