Document Detail

Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer.
MedLine Citation:
PMID:  12600446     Owner:  NLM     Status:  MEDLINE    
Blockade of vascular endothelial growth factor (VEGF) and inhibition of matrix metalloproteinases (MMP) are promising therapies for cancer. This study assessed the effects of a neutralizing anti-VEGF antibody (A4.6.1) and an MMP inhibitor (BB-94) on pancreatic cancer (PaCa) in vivo. Five million cells of two human PaCa cell lines (AsPC-1 and HPAF-2) were injected subcutaneously into nude mice; 1 mm(3) fragments of the resulting tumors were implanted into the pancreas of other mice. Animals were randomized into a control group and three treatment groups: A4.6.1 (100 microg intraperitoneally twice weekly); BB-94 (50 mg/kg every other day); and combination (A4.6.1 plus BB-94). Treatment was started after 3 days and continued for 14 weeks. Tumor volume, local and distant spread (score), and ascites were determined at autopsy. Microvessel density as a parameter of neoangiogenesis was analyzed in CD31-stained tumor sections. Both monotherapies reduced tumor volume (HPAF-2: -89% by A4.6.1 and -75% by BB-94; AsPC-1: -48% by A4.6.1 and -72% by BB-94), spread (HPAF-2: -76% by A4.6.1 and -58% by BB-94; AsPC-1: -32% by A4.6.1 and -54% by BB-94), and microvessel density (HPAF-2: -75% by A4.6.1 and -30% by BB-94; AsPC-1: -59% by A4.6.1 and -30% by BB-94), resulting in a tendency toward increased survival (HPAF-2: 8 of 8 animals by A4.6.1 or BB-94 vs. 4 of 8; AsPC-1: 3 of 8 by A4.6.1, 4 of 8 by BB-94 vs. 1 of 8). Combination therapy yielded additional effects in the HPAF-2 group with regard to tumor volume (-95%) and development of ascites (0 of 8 vs. 2 of 8 by A4.6.1 or BB-94 vs. 5 of 8 control mice). Both VEGF blockade and MMP inhibition reduce primary tumor size, metastasis, and angiogenesis, thereby increasing survival in experimental pancreatic cancer. Combination treatment results in additive effects in moderately differentiated HPAF-2 tumors.
Hubert G Hotz; O Joe Hines; Birgit Hotz; Thomas Foitzik; Heinz J Buhr; Howard A Reber
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract     Volume:  7     ISSN:  1091-255X     ISO Abbreviation:  J. Gastrointest. Surg.     Publication Date:  2003 Feb 
Date Detail:
Created Date:  2003-02-25     Completed Date:  2003-07-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9706084     Medline TA:  J Gastrointest Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  220-7; discussion 227-8     Citation Subset:  IM    
Department of Surgery, UCLA School of Medicine, Los Angeles, CA, USA.
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MeSH Terms
Angiogenesis Inhibitors / pharmacology*
Animals, Newborn
Chi-Square Distribution
Disease Models, Animal
Drug Therapy, Combination
Endothelial Growth Factors
Intercellular Signaling Peptides and Proteins
Lymphokines / drug effects*
Matrix Metalloproteinases / drug effects*
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic / prevention & control*
Pancreatic Neoplasms / drug therapy*,  enzymology
Phenylalanine / analogs & derivatives*,  pharmacology*
Reference Values
Sensitivity and Specificity
Statistics, Nonparametric
Thiophenes / pharmacology*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Endothelial Growth Factors; 0/Intercellular Signaling Peptides and Proteins; 0/Lymphokines; 0/Thiophenes; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors; 130370-60-4/batimastat; 63-91-2/Phenylalanine; EC 3.4.24.-/Matrix Metalloproteinases

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

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