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10.1245/ASO.2003.01.021
Annals of Surgical Oncology 10:762-772 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Gene Therapy of Pancreatic Cancer With Green Fluorescent Protein and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Fusion Gene Expression Driven by a Human Telomerase Reverse Transcriptase Promoter

Matthew H. Katz, MD, Daniel E. Spivack, MD, Shinako Takimoto, BS, Bingliang Fang, MD, PhD, Douglas W. Burton, MS, A.R. Moossa, MD, Robert M. Hoffman, PhD and Michael Bouvet, MD

From the Departments of Surgery (MHK, DS, ST, ARM, RMH, MB) and Medicine (DWB), University of California at San Diego, San Diego, California; Department of Cardiovascular and Thoracic Surgery (BF), University of Texas M. D. Anderson Cancer Center, Houston Texas; and AntiCancer, Inc. (RMH), San Diego, California.

Correspondence: Address correspondence and reprint requests to: Michael Bouvet, MD, Department of Surgery, University of California, San Diego, 3350 La Jolla Village Dr. (112E), San Diego, CA 92161; Fax: 858-552-4352; E-mail: mbouvet{at}ucsd.edu

Background: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in malignant cells but not in normal cells. Ad/g-TRAIL, an adenoviral vector in which expression of green fluorescent protein (GFP) and TRAIL is driven by a human telomerase reverse transcriptase promoter, has shown promise as a targeted antitumor agent.

Methods: To investigate the effects of TRAIL gene therapy on pancreatic cancer, BxPC-3, MIA-PaCa-2, Panc-1, and ASPC-1 cells were treated with Ad/g-TRAIL. Transfection and protein expression were determined by using immunoblotting and identification of GFP with fluorescent microscopy and flow cytometry. Cell viability was determined by proliferation assay. Cell-cycle analysis and quantification of caspase-3 were used to identify apoptosis. The in vivo efficacy of Ad/g-TRAIL was characterized in a novel red fluorescent protein murine model of MIA-PaCa-2 pancreatic cancer.

Results: Cells treated with Ad/g-TRAIL expressed GFP and exhibited apoptotic morphology within 2 days of treatment. Treatment with this vector in vitro resulted in less cell viability, increased caspase-3 activity, and a greater apoptotic fraction than treatment with controls. In vivo, treatment with Ad/g-TRAIL significantly suppressed tumor growth.

Conclusions: TRAIL gene therapy induces apoptosis of pancreatic tumor cells both in vitro and in vivo and is a promising therapy in the treatment of pancreatic cancer.

Key Words: Pancreatic cancer • Gene therapy • TRAIL • GFP • RFP






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