| Sulfasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas. | |
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MedLine Citation:
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PMID: 17143539 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of oncology Volume: 30 ISSN: 1019-6439 ISO Abbreviation: Int. J. Oncol. Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2006-12-04 Completed Date: 2007-01-31 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9306042 Medline TA: Int J Oncol Country: Greece |
Other Details:
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Languages: eng Pagination: 283-90 Citation Subset: IM |
Affiliation:
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Center for Biomedical Integrated Genoproteomics (CBIG) and Center for Cellular and Molecular Neurobiology (CNCM), University of Liège, Belgium. pierre.robe@ulg.ac.be |
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| MeSH Terms | |
Descriptor/Qualifier:
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Bystander Effect
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physiology* Cell Line, Tumor Cell Survival / drug effects Ganciclovir / therapeutic use* Gene Therapy* Glioma / drug therapy, therapy* Humans Simplexvirus / genetics* Sulfasalazine / therapeutic use* Thymidine Kinase / genetics* Tumor Necrosis Factor-alpha / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Tumor Necrosis Factor-alpha; 599-79-1/Sulfasalazine; 82410-32-0/Ganciclovir; EC 2.7.1.21/Thymidine Kinase |
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