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Article (Scientific journals)
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; Princen, Frédéric; Martin, Didier et al.
2000In Biochemical Pharmacology, 60 (2), p. 241-9
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Keywords :
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
Abstract :
[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
Publication date :
15 July 2000
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
eISSN :
1873-2968
Publisher :
Elsevier, Netherlands
Volume :
60
Issue :
2
Pages :
241-9
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 26 November 2010

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