Abstract
Adenoviruses are efficient gene delivery vehicles but have broad native tropism. To this end, finding ways to target this virus specifically to carcinomas has become an important focus of cancer gene therapy. Transductional and transcriptional forms of targeting have been used with promising results in ovarian carcinoma. Therefore, we combined both forms of targeting to investigate the effect on the specificity and efficiency of transgene expression in this disease. We used the tissue-specific SLPI promoter and the ovarian cancer associated targeting adaptor protein, sCARfC6.5. This bispecific protein contains the coxsackie-adenovirus receptor ectodomain and a single-chain antibody specific for c-erbB-2. Viruses containing the SLPI or the ubiquitously expressed CMV promoter, with or without sCARfC6.5, were used for infection of ovarian cancer cell lines, primary ovarian tumor cells, and in an orthotopic model of disseminated ovarian carcinoma. This dual-targeting strategy increased the efficiency and specificity of transgene expression in vitro in reporter and cell-killing assays, and in vivo. By using both the SLPI promoter and sCARfC6.5, transgene expression was increased in ovarian tumors and decreased in normal tissues, including the liver. Thus, we show that combining transcriptional and transductional targeting can increase the efficacy and specificity of adenoviral gene therapy for ovarian carcinoma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Tomko RP, Xu R, Philipson L . The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsakieviruses. Proc Natl Acad Sci USA 1997; 94: 3352–3356.
Yang Y . Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol 1995; 69: 2004–2015.
Yang Y . Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Therapy 1996; 3: 137–144.
Bauerschmitz G, Barker S, Hemminki A . Adenoviral gene therapy for cancer – from vectors to targeted and replication competent agents. Int J Oncol 2002; 21(6): 1164–1174.
Curiel D . Strategies to adapt adenoviral vectors for targeted delivery. Ann NY Acad Sci 1999; 886: 158–171.
Kashentseva E et al. Adenovirus targeting to c-erbB-2 oncoprotein by single-chain antibody fused to trimeric form of adenovirus receptor ectodomain. Cancer Res 2001; 62: 609–616.
Agus D et al. HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer. Semin Oncol 2000; 27: 53–63.
Hung M, Lau Y . Basic science of HER-2/neu: a review. Semin Oncol 1999; 26: 51–59.
Nettelbeck D, Jerome V, Muller R . Gene therapy: designer promoters for tumour targeting. Trends Genet 2000; 16: 174–181.
Barker S et al. The secretory leukoprotease inhibitor (SLPI) promoter for ovarian cancer gene therapy. J Gene Med 2002; (in press).
Kanerva A et al. Gene transfer to ovarian cancer versus normal tissues with fiber modified adenoviruses. Mol Ther 2002; 5: 695–704.
Reynolds P et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotech 2001; 19: 838–842.
Robertson M et al. Use of a tissue-specific promoter for targeted expression of the herpes simplex virus thymidine kinase gene in cervical carcinoma cells. Cancer Gene Ther 1998; 5: 331–336.
Barker S et al. (2002). The regulatory sequences of the secretory leukoprotease inhibitor gene as a promising tissue-specific promoter for ovarian cancer gene therapy. In: American Society of Gene Therapy. Boston, MA.
Barker S et al. An immunomagnetic-based method for the purification of ovarian cancer cells from patient-derived ascites. Gynecol Oncol 2001; 82: 57–63.
Raper S et al. A pilot study on in vivo-directed gene transfer with an adenoviral vector in partial orthinine transcarbamylase defiency. Hum Gene Ther 2002; 13: 163–175.
Casado E et al. Transcriptional targeting for ovarian cancer gene therapy. Gynecol Oncol 2001; 82: 229–237.
Qiao J et al. Tumor-specific transcriptional targeting of suicide gene therapy. Gene Therapy 2002; 9: 168–175.
Acknowledgements
The study was supported by the Sigrid Juselius Foundation, the Emil Aaltonen Foundation, the Maud Kuistila Foundation, the Finnish Medical Foundation, the Academy of Finland and the National Cancer Institute (CA83821, P50 CA83591, P50 CA89019), US Army Department of Defense (DAMD17-00-1–0115), and the Deutsche Forschungsgemeinschaft.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barker, S., Dmitriev, I., Nettelbeck, D. et al. Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma. Gene Ther 10, 1198–1204 (2003). https://doi.org/10.1038/sj.gt.3301974
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301974
Keywords
This article is cited by
-
Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution
Gene Therapy (2011)
-
Carboxypeptidase G2-based gene-directed enzyme–prodrug therapy: a new weapon in the GDEPT armoury
Nature Reviews Cancer (2007)
-
Engineering conditionally replication-competent adenoviral vectors carrying the cytosine deaminase gene increases the infectivity and therapeutic effect for breast cancer gene therapy
Cancer Gene Therapy (2006)
-
Comprehensive analysis of HE4 expression in normal and malignant human tissues
Modern Pathology (2006)
-
Mesothelin-mediated targeting of adenoviral vectors for ovarian cancer gene therapy
Gene Therapy (2005)