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
[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.
Disciplines :
Surgery
Author, co-author :
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Princen, Frédéric
Martin, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Neurochirurgie
Malgrange, Brigitte ; Université de Liège - ULiège > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc.
Stevenaert, Achille ; Université de Liège - ULiège > Services généraux (Faculté de médecine) > Relations académiques et scientifiques (Médecine)
Moonen, Gustave ; Université de Liège - ULiège > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine
Gielen, Jean-Louis ; Centre Hospitalier Universitaire de Liège - CHU > Chirurgie maxillo-faciale et plastique
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Language :
English
Title :
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
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