Document Detail


VEGF antisense therapy inhibits tumor growth and improves survival in experimental pancreatic cancer.
MedLine Citation:
PMID:  15674201     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, is overexpressed in pancreatic cancer. This study evaluated VEGF production in pancreatic cancer cells and the effect of VEGF antisense on growth and angiogenesis of human pancreatic cancer in a nude mouse model. METHODS: In vitro: VEGF in cell culture supernatant of pancreatic cancer cells (AsPC-1, poorly differentiated; HPAF-2, moderately differentiated) was assessed by enzyme-linked immunosorbent assay. In vivo: A VEGF antisense oligonucleotide (AS-3) was synthesized. One-mm(3) fragments of subcutaneous pancreatic cancer donor tumors were implanted into the pancreas of nude mice also receiving AS-3 (10 mg/kg/day) or vehicle intraperitoneally for 14 weeks. Primary tumor volume, metastasis, and VEGF in plasma and ascites were determined at autopsy. Microvessel density was analyzed in CD31-stained tumors. RESULTS: In vitro: Both pancreatic cancer cell lines secreted VEGF protein (AsPC-1, 4200 +/- 40 pg/10(6) cells; HPAF-2, 8120 +/- 60 pg/10(6) cells). In vivo: AS-3 reduced tumor volume in the HPAF-2 group (860 +/- 140 vs 3830 +/- 590 mm(3)) and metastatic spread in both groups (AsPC-1, 6.5 +/- 0.8 vs 16.7 +/- 0.9 points; HPAF-2, 2.5 +/- 0.2 vs 8.3 +/- 1.5 points). Tumor volume was not different in the AsPC-1 group (1050 +/- 80 vs 1400 +/- 150 mm(3)). Survival was increased in the AsPC-1 group. Plasma levels of VEGF and microvessel density in tumors were significantly reduced in treated animals. Only control animals (50%) developed ascites with high VEGF concentrations. CONCLUSIONS: Human pancreatic cancer cells secrete VEGF at biologically relevant high levels. AS-3 therapy normalizes plasma VEGF and decreases neoangiogenesis, thereby reducing tumor growth and metastasis and improving survival. AS-3-treated animals developed no ascites, suggesting decreased vascular permeability by reducing VEGF expression in pancreatic cancer cells.
Authors:
Hubert G Hotz; O Joe Hines; Rizwan Masood; Birgit Hotz; Thomas Foitzik; Heinz J Buhr; Parkash S Gill; Howard A Reber
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Surgery     Volume:  137     ISSN:  0039-6060     ISO Abbreviation:  Surgery     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-27     Completed Date:  2005-03-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0417347     Medline TA:  Surgery     Country:  United States    
Other Details:
Languages:  eng     Pagination:  192-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Surgery, School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. hhotz@zedat.fu-berlin.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Ascites / metabolism
Base Sequence
Cell Line, Tumor
Disease Models, Animal
Humans
Male
Mice
Mice, Nude
Microcirculation / pathology
Neoplasm Transplantation
Oligodeoxyribonucleotides, Antisense / genetics,  therapeutic use*
Pancreatic Neoplasms / blood supply,  metabolism,  pathology,  therapy*
Transplantation, Heterologous
Vascular Endothelial Growth Factor A / antagonists & inhibitors*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/Oligodeoxyribonucleotides, Antisense; 0/Vascular Endothelial Growth Factor A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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