1. ¹Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Research Pavilion, Suite 5090, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
2. ²Molecular Medicine and Gene Therapy Unit, School of Medicine, University of Manchester, Manchester M13 9PT, UK
3. ³Department of Neurology, School of Medicine, University of Tubingen, Tubingen, Germany
4. ⁴Department of Medicine, and Department of Molecular Pharmacology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), USA

Correspondence: Dr Pedro R Lowenstein MD, PhD, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Research Pavilion, Suite 5090, 8700 Beverly Boulevard, Los Angeles, California 90048, USA. E-mail: lowensteinp@cshs.org; Dr Maria G Castro PhD, castromg@cshs.org

Received 27 January 2004; Published online 8 October 2004.

Abstract

Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor- (TGF-) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats.

We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (P<.0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (P<.0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.