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.
abstract: 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.
authors.affiliation: Department of Neurosurgery, University of Liège, Liège, Belgium. Pierre.Robe@ulg.ac.be
authors.forename: P A
authors.initials: PA
authors.lastname: Robe
authors.forename: F
authors.initials: F
authors.lastname: Princen
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: B
authors.initials: B
authors.lastname: Malgrange
authors.forename: A
authors.initials: A
authors.lastname: Stevenaert
authors.forename: G
authors.initials: G
authors.lastname: Moonen
authors.forename: J
authors.initials: J
authors.lastname: Gielen
authors.forename: M
authors.initials: M
authors.lastname: Merville
authors.forename: V
authors.initials: V
authors.lastname: Bours
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D018031:Connexin 43 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000096:biosynthesis; D003561:Cytarabine / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects; D015316:Genetic Therapy; D005909:Glioblastoma; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018031:Connexin 43; D017630:Connexins; D012333:RNA, Messenger; D003561:Cytarabine; D003994:Bucladesine; D013937:Thymidine Kinase; D006034:Glycyrrhetinic Acid; D015774:Ganciclovir