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.
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.
Robe
P A
PA
Department of Neurosurgery, University of Liège, Liège, Belgium. Pierre.Robe@ulg.ac.be
Princen
F
F
Martin
D
D
Malgrange
B
B
Stevenaert
A
A
Moonen
G
G
Gielen
J
J
Merville
M
M
Bours
V
V
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
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