Reference : Pharmacological Modulation of the Bystander Effect in the Herpes Simplex Virus Thymid...
Scientific journals : Article
Human health sciences : Surgery
Pharmacological Modulation of the Bystander Effect in the Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy System: Effects of Dibutyryl Adenosine 3',5'-Cyclic Monophosphate, Alpha-Glycyrrhetinic Acid, and Cytosine Arabinoside
Robe, Pierre mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques >]
Princen, Frédéric [> > > >]
Martin, Didier mailto [Université de Liège - ULg > Département des sciences cliniques > Neurochirurgie]
Malgrange, Brigitte mailto [Université de Liège - ULg > > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc. >]
Stevenaert, Achille mailto [Université de Liège - ULg > Services généraux (Faculté de médecine) > Relations académiques et scientifiques (Médecine) >]
Moonen, Gustave mailto [Université de Liège - ULg > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine]
Gielen, Jean-Louis mailto [Centre Hospitalier Universitaire de Liège - CHU > > Chirurgie maxillo-faciale et plastique >]
Merville, Marie-Paule mailto [Université de Liège - ULg > Département de pharmacie > Chimie médicale >]
Bours, Vincent mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Génétique générale et humaine]
Biochemical Pharmacology
Yes (verified by ORBi)
[en] Animals ; Antimetabolites, Antineoplastic/pharmacology ; Antineoplastic Agents/administration & dosage/pharmacology ; Bucladesine/pharmacology ; Connexin 43/biosynthesis/genetics/metabolism ; Connexins/biosynthesis ; Cytarabine/pharmacology ; Drug Screening Assays, Antitumor ; Ganciclovir/administration & dosage/pharmacology ; Gap Junctions/drug effects ; Gene Therapy ; Glioblastoma ; Glycyrrhetinic Acid/pharmacology ; Phosphorylation ; RNA, Messenger/biosynthesis ; Rats ; Simplexvirus/enzymology ; Thymidine Kinase/genetics/metabolism ; Transfection ; Tumor Cells, Cultured
[en] The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the bystander effect, thus confirming the role of gap junctions in HSV-tk-mediated bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the bystander effect.

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Biochemical Pharmacology 60 (2000) 241-249 - Robe - Bystander effect.pdfNo commentaryPublisher postprint578.67 kBRequest copy

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