Document Detail

Sulfasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas.
MedLine Citation:
PMID:  17143539     Owner:  NLM     Status:  MEDLINE    
The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased the HSV-TK/ganciclovir bystander effect in C6, 9L and LN18 cells but not in U87 glioma cells. Using bi-compartmental culture devices and conditioned medium transfer experiments, we showed that in C6, 9L and LN18 cells but not in U87 cells, Sulfasalazine also unveiled a new, contact-independent mechanism of HSV-TK/ganciclovir bystander effect. Upon treatment with ganciclovir, human LN18-TK but not U87-TK cells synthetized and released TNF-alpha in the culture medium. Sulfasalazine sensitized glioma cells to the toxic effect of TNF-alpha and enhanced its secretion in LN18-TK cells in response to GCV treatment. The caspase-8 inhibitor Z-IETD-FMK and a blocking antibody to TNF-alpha both inhibited the contact-independent bystander effect in LN18 cells. Taken together, these results suggest that TNF-alpha mediates the contact-independent bystander effect in LN18 cells. The treatment with GCV and/or Sulfasalazine of tumor xenografts consisting of a mix of 98% C6 and 2% C6-TK cells shows that Sulfasalazine is also a potent adjunct to the in vivo treatment of gliomas.
Pierre A Robe; Minh-Tuan Nguyen-Khac; Frederic Lambert; Chantal Lechanteur; Olivier Jolois; Patricia Ernst-Gengoux; Bernard Rogister; Vincent Bours
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  30     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-04     Completed Date:  2007-01-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  283-90     Citation Subset:  IM    
Center for Biomedical Integrated Genoproteomics (CBIG) and Center for Cellular and Molecular Neurobiology (CNCM), University of Liège, Belgium.
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MeSH Terms
Bystander Effect / physiology*
Cell Line, Tumor
Cell Survival / drug effects
Ganciclovir / therapeutic use*
Gene Therapy*
Glioma / drug therapy,  therapy*
Simplexvirus / genetics*
Sulfasalazine / therapeutic use*
Thymidine Kinase / genetics*
Tumor Necrosis Factor-alpha / metabolism
Reg. No./Substance:
0/Tumor Necrosis Factor-alpha; 599-79-1/Sulfasalazine; 82410-32-0/Ganciclovir; EC Kinase

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