%0 Journal Article
%T Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells
%A Pierre A Robe
%A Minh Nguyen-Khac
%A Olivier Jolois
%A Bernard Rogister
%A Marie-Paule Merville
%A Vincent Bours
%J BMC Cancer
%D 2005
%I BioMed Central
%R 10.1186/1471-2407-5-32
%X 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 BclXL.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.The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.Herpes Simplex virus thymidine kinase gene (HSV-tk) suicide gene therapy has lately been used in a variety of cancer models to sensitize replicating cells to the antiviral drug ganciclovir (GCV) [1-3]. In this paradigm, tumor cells transfected with the HSV-tk gene become able to mono-phosphorylate ganciclovir, a nucleotide analog. Ganciclovir monophosphate is subsequently bis and tri-phosphorylated by cellular kinases and is then incorporated in the DNA of replicating cells, blocking the cell cycle and inducing apoptosis [1,4,5]. Cells that are transfected and exposed to ganciclovir can also kill adjacent, untransfected cells by the so-called bystander effect. In most tumor types, the bystander effect relies on the transfer of phosphorylated gan
%U http://www.biomedcentral.com/1471-2407/5/32