Document Detail


Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable oncolytic measles virus.
MedLine Citation:
PMID:  20858718     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Primary and secondary cancers of the liver are a significant health problem with limited treatment options. We sought here to develop an oncolytic measles virus (MV) preferentially activated in liver tumor tissue, thus reducing infection and destruction of healthy tissue. We documented that in primary tumor tissue, urokinase-type plasminogen activator and especially matrix metalloproteinase-2 (MMP-2) are significantly more active than in adjacent nontumorous tissue. We then generated variants of the MV fusion protein by inserting different MMP substrate motifs at the protease cleavage site and identified the motif PQGLYA as the most efficient cleavage site as determined by syncytia formation on protease-positive tumor cells. The corresponding MMP-activatable oncolytic MV-MMPA1 virus was rescued and shown to be strongly restricted on primary human hepatocytes and healthy human liver tissue, while remaining as effective as the parental MV in the tumor tissue sections. Our findings underline the clinical potency of the MMP activation concept as a strategy to generate safer oncolytic viruses for the treatment of primary and secondary cancers of the liver.
Authors:
Michael D Mühlebach; Thomas Schaser; Martina Zimmermann; Sorin Armeanu; Kay-Martin O Hanschmann; Roberto Cattaneo; Michael Bitzer; Ulrich M Lauer; Klaus Cichutek; Christian J Buchholz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-21
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7620-9     Citation Subset:  IM    
Copyright Information:
© 2010 AACR.
Affiliation:
Division of Medical Biotechnology and Biostatistics Section, Paul-Ehrlich-Institut, Langen, Germany.
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