Tumorsuppression durch ein RGD modifiziertes, hTERT reguliertes, TRAIL exprimierendes Adenovirus in einem orthotopen Pankreas Tumormodell

Abstract

We recently demonstrated the antitumor activity of a recombinant, non-replicating adenovector expressing the green fluorescent protein (GFP)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) fusion gene from the human telomerase reverse transcriptase (hTERT) promoter in various cancer cells and animal tumor models. Despite these promising results, adenovirus-mediated gene delivery is limited to cells with cell surface receptors for viral entry. However, modified adenoviruses containing an RGD motif in the HI loop of the fiber protein can be efficiently transferred into cell lines with little or no coxsackie-adenovirus receptor (CAR) expression. Therefore, fiber-modified adenovectors may have broad application for cancer therapy. We constructed an adenoviral vector with RGD-modified fibers and expressing the human TRAIL gene from the hTERT promoter (designated Ad/TRAIL-F/RGD). An in vitro study showed that treatment with Ad/TRAIL-F/RGD elicited high levels of transgene expression and a high rate of apoptosis in human pancreatic and colon cancer cell lines. An vivo study showed that direct administration of Ad/TRAIL-F/RGD to an orthotopic pancreatic tumor model significantly suppressed tumor growth: tumors in animals treated with Ad/TRAIL-F/RGD were about 7 times smaller than tumors in animals treated with a control vector. Our results suggest that Ad/TRAIL-F/RGD may be a potent therapeutic agent for the treatment of pancreatic cancer.