THE DRUG VERAPAMIL INHIBITS BYSTANDER KILLING BUT NOT CELL SUICIDE INTHYMIDINE KINASE GANCICLOVIR PRODRUG-ACTIVATED GENE-THERAPY

The bystander effect, in which unmodified cells are killed as the resu lt of enzyme-prodrug activation in genetically modified neighboring ce lls, amplifies the suicide response in a tumor in which only a fractio n of the cells are targeted. The drug verapamil (VRP), a calcium chann el antagonist that is also used to counteract the multidrug resistance of tumor cells, is shown to inhibit the bystander effect by herpes si mplex virus thymidine kinase (HSVtk) enzyme-prodrug therapy with ganci clovir by protecting beta geo marked bystander cells in both in vitro coculture assays and in an in vivo animal tumor model. VRP had no stim ulatory or inhibitory effect on the proliferation of CT 26 cells, thei r tumorigenicity, or prodrug-activated cell death produced by the acti on of the HSVtk gene. The kinetics of the protection afforded by VRP w as time dependent with respect to the time of addition of the prodrug, and protection was ineffective when added two or more days after prod rug administration.