The drug verapamil inhibits bystander killing but not cell suicide in thymidine kinase-ganciclovir prodrug-activated gene therapy.
The bystander effect, in which unmodified cells are killed as the result of enzyme-prodrug activation in genetically modified neighboring cells, amplifies the suicide response in a tumor in which only a fraction of the cells are targeted. The drug verapamil (VRP), a calcium channel antagonist that is also used to counteract the multidrug resistance of tumor cells, is shown to inhibit the bystander effect by herpes simplex virus thymidine kinase (HSVtk) enzyme-prodrug therapy with ganciclovir by protecting beta geo marked bystander cells in both in vitro coculture assays and in an in vivo animal tumor model. VRP had no stimulatory or inhibitory effect on the proliferation of CT 26 cells, their tumorigenicity, or prodrug-activated cell death produced by the action of the HSVtk gene. The kinetics of the protection afforded by VRP was time dependent with respect to the time of addition of the prodrug, and protection was ineffective when added two or more days after prodrug administration.
Marini
F C
FC
Department of Experimental Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Pan
B F
BF
Nelson
J A
JA
Lapeyre
J N
JN
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D012190:Retroviridae / Q000201:enzymology; D013937:Thymidine Kinase / Q000378:metabolism*; D014162:Transfection / Q000235:genetics; D014700:Verapamil / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D014700:Verapamil; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir