In vivo gene transfer of pigment epithelium-derived factor inhibits tumor growth in syngeneic murine models of thoracic malignancies.
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 (beta-galactosidase). One day later, treatment (phosphate-buffered saline, AdNull, or AdPEDF) was administered intrapleurally. Tumor burden (gross and histologic inspection, lung weight, and beta-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), beta-galactosidase expression (P <.05), and animal survival was prolonged (P <.05).


CONCLUSIONS
Gene transfer of pigment epithelium-derived factor suppresses tumor vascularization and growth, while prolonging survival in syngeneic murine models of thoracic malignancies.
Mahtabifard
Ali
A
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Merritt
Robert E
RE
Yamada
Reiko E
RE
Crystal
Ronald G
RG
Korst
Robert J
RJ
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D004195:Disease Models, Animal; D005136:Eye Proteins; D005260:Female; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008955:Models, Cardiovascular; D009414:Nerve Growth Factors; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015843:Serpins / Q000096:biosynthesis / Q000235:genetics*; D016019:Survival Analysis; D013899:Thoracic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D014407:Tumor Cells, Cultured; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor