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Differential Vascular and Transcriptional Responses to Anti-Vascular Endothelial Growth Factor Antibody in Orthotopic Human Pancreatic Cancer Xenografts¹

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [M. B., Y. T., L. X., D. F.], and Department of General and Transplantation Surgery, University Hospital Essen, Essen 45122, Germany [M. B., A. F., C. E. B.]

Purpose: The objectives of this study were to investigate the effects of anti-vascular endothelial growth factor (VEGF) treatment on various vascular functions, gene expression, and growth of orthotopic human pancreatic cancer xenografts and thus to provide useful preclinical data for novel cancer treatments.

Experimental Design: Small pieces of a human pancreatic carcinoma, PANC-1, were implanted into the pancreas of male severe combined immunodeficient mice. The animals were treated with anti-human VEGF antibody A.4.6.1 (300 µg, every 3 days i.p.) or a nonspecific IgG between 4 and 8 weeks after tumor implantation. Then, vascular density, diameter, permeability, and tumor growth were determined by intravital microscopy. Subsequently, tumors were harvested, and angiogenic gene expression profile was determined by a microarray kit including 96 genes involved in tumor angiogenesis.

Results: Anti-VEGF antibody significantly reduced angiogenesis and growth of orthotopic PANC-1 tumors. In the anti-VEGF treatment group, the vessel density was significantly smaller (67.8 ± 10.6 cm/cm²) than that seen in the control group (146.7 ± 10.0 cm/cm²). However, vessel diameter and permeability were not altered significantly by anti-VEGF antibody treatment. The pancreatic tumors in the treated group were significantly smaller than those in the control group. Microarray and subsequent Northern blot and semiquantitative reverse transcription-PCR analyses revealed both a decrease (fibroblast growth factor 1, transforming growth factor ß1, platelet-derived growth factor , erbB2, and c-ets1,) and an increase (placenta growth factor, hypoxia-inducible factor , and endoglin) in expression of angiogenesis-related genes in the PANC-1 tumors by anti-VEGF treatment.

Conclusions: Anti-VEGF antibody treatment has differential effects on vessel functions as well as angiogenic gene expression and inhibitory effects on angiogenesis and growth of the orthotopic pancreatic tumor. Anti-VEGF strategy appears promising for pancreatic cancer treatment.

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