Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells
<p>Abstract</p> <p>Background</p> <p>HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2005-04-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/5/32 |
| _version_ | 1818273216143032320 |
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| author | Jolois Olivier Nguyen-Khac Minh Robe Pierre A Rogister Bernard Merville Marie-Paule Bours Vincent |
| author_facet | Jolois Olivier Nguyen-Khac Minh Robe Pierre A Rogister Bernard Merville Marie-Paule Bours Vincent |
| author_sort | Jolois Olivier |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed.</p> <p>Methods</p> <p>Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and Bcl<sub>XL</sub>.</p> <p>Results</p> <p>Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade.</p> <p>Conclusion</p> <p>The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment <it>in vitro</it>. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.</p> |
| first_indexed | 2024-12-12T21:54:26Z |
| format | Article |
| id | doaj.art-4099f4b42ac14aec94b0f8ae7e573aa6 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-12T21:54:26Z |
| publishDate | 2005-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-4099f4b42ac14aec94b0f8ae7e573aa62022-12-22T00:10:42ZengBMCBMC Cancer1471-24072005-04-01513210.1186/1471-2407-5-32Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cellsJolois OlivierNguyen-Khac MinhRobe Pierre ARogister BernardMerville Marie-PauleBours Vincent<p>Abstract</p> <p>Background</p> <p>HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed.</p> <p>Methods</p> <p>Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and Bcl<sub>XL</sub>.</p> <p>Results</p> <p>Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade.</p> <p>Conclusion</p> <p>The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment <it>in vitro</it>. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.</p>http://www.biomedcentral.com/1471-2407/5/32 |
| spellingShingle | Jolois Olivier Nguyen-Khac Minh Robe Pierre A Rogister Bernard Merville Marie-Paule Bours Vincent Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells BMC Cancer |
| title | Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells |
| title_full | Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells |
| title_fullStr | Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells |
| title_full_unstemmed | Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells |
| title_short | Dexamethasone inhibits the HSV-<it>tk</it>/ ganciclovir bystander effect in malignant glioma cells |
| title_sort | dexamethasone inhibits the hsv it tk it ganciclovir bystander effect in malignant glioma cells |
| url | http://www.biomedcentral.com/1471-2407/5/32 |
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