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J Thorac Cardiovasc Surg 2003;126:28-38
© 2003 The American Association for Thoracic Surgery

General thoracic surgery

In vivo gene transfer of pigment epithelium-derived factor inhibits tumor growth in syngeneic murine models of thoracic malignancies

^a Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center,, New York, NY, USA
^b Department of Cardiothoracic Surgery,, New York, NY, USA
^c Division of Pulmonary and Critical Care Medicine, New York, NY, USA
^d Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, USA

Received for publication August 6, 2002; revisions received September 12, 2002; accepted for publication September 23, 2002.

^* Address for reprints: Robert J. Korst, MD, Department of Cardiothoracic Surgery, M 404, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA
rjk2002{at}med.cornell.edu

OBJECTIVE: Pigment epithelium-derived factor is known to be an inhibitor of angiogenesis. We hypothesized that in vivo gene transfer of pigment epithelium-derived factor may inhibit tumor angiogenesis and growth in syngeneic models of thoracic malignancies.

METHODS: An adenovirus vector encoding the human pigment epithelium-derived factor cDNA (AdPEDF) was used to transduce human lung cancer cells in vitro. Transgene expression was assessed using Western analysis. Three different murine flank tumors (2 lung, 1 colon) were then established in syngeneic mice and treated intratumorally with phosphate-buffered saline, AdPEDF, or an empty vector (AdNull). Endpoints measured included transgene expression, tumor size, and animal survival, as well as microvessel density within the tumor. Additionally, a murine pulmonary metastasis model was established by intravenous injection of a syngeneic colon adenocarcinoma cell line expressing a marker gene (ß-galactosidase). One day later, treatment (phosphate-buffered saline, AdNull, or AdPEDF) was administered intrapleurally. Tumor burden (gross and histologic inspection, lung weight, and ß-galactosidase expression) was then evaluated 13 days after vector dosing, and survival was recorded.

RESULTS: AdPEDF-derived expression of pigment epithelium-derived factor was demonstrated in vitro and in vivo. In syngeneic murine lung cancer flank tumors, intratumoral administration of AdPEDF significantly inhibited tumor growth (P < .01), prolonged mouse survival (P < .01), and decreased microvessel density (P < .01) compared with control groups. In the pulmonary metastasis model, AdPEDF-treated mice exhibited significantly reduced lung lesions, lung weight (P < .0005), ß-galactosidase expression (P < .05), and animal survival was prolonged (P < .05).

CONCLUSION: Gene transfer of pigment epithelium-derived factor suppresses tumor vascularization and growth, while prolonging survival in syngeneic murine models of thoracic malignancies.

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