Document Detail

Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer.
MedLine Citation:
PMID:  17356708     Owner:  NLM     Status:  MEDLINE    
PURPOSE: PD173074, a small molecule inhibitor of VEGF-RII and FGF-RI, targets neoangiogenesis and mitogenesis. This study aimed to analyze a single-compound-driven inhibition of FGF and VEGF receptors in pancreatic cancer.
EXPERIMENTAL DESIGN: RT-PCR and Western blots were performed to quantify protein expression and phosphorylation. Anchorage dependent and independent growth assays were used to study cell growth. With flow cytometry, cell cycle analysis and apoptosis were studied. In vivo HPAF-II and MIA PaCa-2 cells were xenografted. Animals were treated daily for 10 weeks. Immunohistochemistry was used to quantify microvessel density and apoptosis.
RESULTS: Highest levels of FGF-RI were detectable in MIA PaCa-2 cells, lowest in HPAF-II cells. PD173074 inhibited cell growth most prominently in cells expressing high levels of FGF-RI. Cell cycle progression was inhibited by blocking transition in the G(0)/G(1) phase, and consequently, apoptosis was increased. In vivo significant inhibition of orthotopic tumor growth was achieved by a combination effect of inhibition of mitogenesis, induction of apoptosis, and reduction of angiogenesis in PD173074-treated animals.
CONCLUSIONS: These data highlight VEGF-RII and FGF-RI as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable pancreatic cancer patients.
Peter Büchler; Howard A Reber; Mendel M Roth; Mark Shiroishi; Helmut Friess; Oscar J Hines
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  9     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-03-14     Completed Date:  2007-04-12     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  119-27     Citation Subset:  IM    
Department of Surgery, UCLA School of Medicine, University of California, Los Angeles, CA 90095-6904, USA.
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MeSH Terms
Angiogenesis Inhibitors / administration & dosage,  pharmacology,  therapeutic use*
Antineoplastic Agents / administration & dosage,  pharmacology,  therapeutic use*
Apoptosis / drug effects
Carcinoma / blood supply,  drug therapy*,  metabolism
Cell Cycle / drug effects
Cell Division / drug effects
Cell Line, Tumor / drug effects,  transplantation
Mice, Inbred BALB C
Mice, Nude
Neoplasm Proteins / antagonists & inhibitors*,  biosynthesis,  genetics
Pancreatic Neoplasms / blood supply,  drug therapy*,  metabolism
Protein Kinase Inhibitors / administration & dosage,  pharmacology,  therapeutic use*
Pyrimidines / administration & dosage,  pharmacology,  therapeutic use*
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*,  biosynthesis,  genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Stem Cell Assay
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*,  biosynthesis,  genetics
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Antineoplastic Agents; 0/Neoplasm Proteins; 0/PD 173074; 0/Protein Kinase Inhibitors; 0/Pyrimidines; EC protein, human; EC, Fibroblast Growth Factor, Type 1; EC Endothelial Growth Factor Receptor-2

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