Document Detail


Cytotoxic effects of vascular smooth muscle cells of the chimeric toxin, heparin binding TGF alpha-Pseudomonas exotoxin.
MedLine Citation:
PMID:  8287449     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Smooth muscle cell proliferation appears to be very important in restenosis after angioplasty. A chimeric toxin created by genetically fusing the gene encoding TGF alpha (targets the EGF receptor) to the gene encoding Pseudomonas exotoxin (PE) preferentially kills rapidly proliferating smooth muscle cells. Recently, a heparin binding EGF-like growth factor (HB-EGF) has been identified. The HB domain enhances the mitogenic activity for smooth muscle cells. The purpose of this study was to design a new chimeric toxin, having both heparin binding and EGF receptor binding function, and to determine whether it is more cytotoxic to smooth muscle cells. METHODS: By recombinant DNA techniques, a new chimeric toxin, HB-TGF alpha-PE4EKDEL, was synthesised. Cytotoxic assays were performed by assessing the capacity to inhibit protein synthesis of rat vascular smooth muscle cells. RESULTS: The toxin preferentially killed rapidly proliferating smooth muscle cells (p < 0.025). The HB domain increased the cytotoxicity of the molecule when compared to the other chimeric toxins tested against smooth muscle cells. The cytotoxic effect of the new molecule was significantly decreased by exogenously added heparin (p < 0.05). CONCLUSIONS: The presence of a heparin binding domain increases the smooth muscle cell cytotoxicity of the TGF alpha fusion toxin, perhaps because HB-TGF alpha-PE4EKDEL functions as a molecule with two ligands. It will be important to determine whether the greater smooth muscle cell cytotoxicity that exists in vitro will facilitate the specific targeting and killing of rapidly proliferating cells in vivo.
Authors:
Y M Fu; E A Mesri; Z X Yu; R J Kreitman; I Pastan; S E Epstein
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Cardiovascular research     Volume:  27     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  1993 Sep 
Date Detail:
Created Date:  1994-02-22     Completed Date:  1994-02-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1691-7     Citation Subset:  IM    
Affiliation:
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Division / drug effects
Cells, Cultured
Exotoxins / pharmacology*
Heparin / metabolism
Immunotoxins / pharmacology*
Leucine / metabolism
Muscles / cytology,  drug effects*,  metabolism
Protein Binding
Rats
Rats, Sprague-Dawley
Receptor, Epidermal Growth Factor / metabolism
Recombinant Fusion Proteins / pharmacology*
Transforming Growth Factor alpha / pharmacology*
Chemical
Reg. No./Substance:
0/Exotoxins; 0/Immunotoxins; 0/Recombinant Fusion Proteins; 0/Transforming Growth Factor alpha; 0/transforming growth factor(alpha)-Pseudomonas exotoxin A (35); 61-90-5/Leucine; 9005-49-6/Heparin; EC 2.7.10.1/Receptor, Epidermal Growth Factor

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


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