Document Detail

G3139 antisense oligonucleotide directed against antiapoptotic Bcl-2 enhances doxorubicin cytotoxicity in the FU-SY-1 synovial sarcoma cell line.
MedLine Citation:
PMID:  16450387     Owner:  NLM     Status:  MEDLINE    
Synovial sarcoma (SS) is a highly aggressive, periarticular soft tissue sarcoma that causes death in more than half of affected children, adolescents, and young adults. Five- and 10-year survival rates are as low as 36 and 20%, respectively. Bcl-2, a negative regulator of apoptosis, is overexpressed in up to 90% of SS. Increased Bcl-2 expression not only leads to the development of cancer, but also to resistance of many anticancer chemotherapeutic agents. We hypothesized reducing Bcl-2 expression in SS should enhance doxorubicin cytotoxicity. Cell cultures representing two human sarcomas (FU-SY-1 SS and the pleomorphic SW982) and a primary human dermal fibroblast comparator (NHDF) were exposed in vitro to doxorubicin, or to doxorubicin preceded by Bcl-2 (G3139) antisense oligonucleotides, and assayed for cell survival, apoptosis, and modulations in Bcl-2 and Bcl-xL mRNA and protein content. SW982 sarcoma cells proved most susceptible to doxorubicin, while NHDF mesenchymal cells were least sensitive to doxorubicin. Treatment of FU-SY-1 SS with G3139 reduced Bcl-2 mRNA and protein levels, which enhanced doxorubicin-induced cell killing. There was a concurrent reduction in Bcl-xL mRNA following G3139 application in FU-SY-1 and NHDF cultures, but not in SW982. G3139 anti-Bcl-2 intervention sensitized the FU-SY-1 SS to doxorubicin, due to increased apoptosis. G3139 intervention was ineffective in the two non-SS cell lines.
David E Joyner; Karen H Albritton; Jeffrey D Bastar; R Lor Randall
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of orthopaedic research : official publication of the Orthopaedic Research Society     Volume:  24     ISSN:  0736-0266     ISO Abbreviation:  J. Orthop. Res.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-27     Completed Date:  2006-04-13     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8404726     Medline TA:  J Orthop Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  474-80     Citation Subset:  IM    
Copyright Information:
Copyright 2006 Orthopaedic Research Society.
SARC Laboratory, Sarcoma Services, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, Utah 84112, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Doxorubicin / pharmacology*
Drug Synergism
Gene Expression Regulation, Neoplastic / drug effects
Oligonucleotides, Antisense / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / genetics*,  metabolism
RNA, Messenger / analysis
Reverse Transcriptase Polymerase Chain Reaction
Sarcoma, Synovial / drug therapy*,  metabolism,  pathology
Soft Tissue Neoplasms / drug therapy*,  metabolism,  pathology
Reg. No./Substance:
0/Antineoplastic Agents; 0/Oligonucleotides, Antisense; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 23214-92-8/Doxorubicin

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