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Adenovirus delivery of human CD40 ligand gene confers direct therapeutic effects on carcinomas
University of Crete Medical School.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
University of Crete Medical School.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2009 (English)In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 16, no 11, 848-860 p.Article in journal (Refereed) Published
Abstract [en]

 CD40, a tumor necrosis factor receptor family member, is an emerging   target for cancer therapy being best appreciated as an important   regulator of the anti-tumor immune response. In this study, we report   the development of a replication-defective recombinant adenovirus (RAd)   vector expressing human CD40 ligand (RAd-hCD40L) and show that   sustained engagement of the CD40 pathway in malignant cells results in   direct anti-proliferative and pro-apoptotic effects. Thus, transduction   of CD40-positive bladder, cervical and ovarian carcinoma cell lines   with RAd-hCD40L potently inhibits their proliferation in vitro, whereas   CD40-negative lines remain unresponsive. RAd-hCD40L is also found to be   superior to recombinant CD40L in inducing carcinoma cell death and in   amplifying the cytotoxic effects of the chemotherapeutic agents   5-fluorouracil, cis-platin and mitomycin C. Soluble CD40L is produced   by RAd-hCD40L transduced carcinoma cells but unlike other soluble tumor   necrosis factor family ligands, it does not interfere with the   death-promoting activity of its membrane-bound form. In a mouse   xenograft tumor model bearing a human bladder carcinoma, intratumoral   delivery of RAd-hCD40L suppresses cancer growth. These findings   highlight the potential of exploiting the CD40 pathway in carcinomas   using CD40L gene transfer alone or in combination with other modalities   for cancer therapy. Our results have also broader implications in   understanding the multifaceted anti-tumor activities of the CD40   pathway in carcinomas, which thus offer an attractive option for future   clinical application.

Place, publisher, year, edition, pages
2009. Vol. 16, no 11, 848-860 p.
Keyword [en]
CD40, CD154, gene therapy, carcinoma, apoptosis, adenovirus
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-110785DOI: 10.1038/cgt.2009.31ISI: 000270956100006OAI: oai:DiVA.org:uu-110785DiVA: diva2:278339
Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-12-12Bibliographically approved

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