MECHANISM OF BYSTANDER EFFECT KILLING IN THE HERPES-SIMPLEX THYMIDINEKINASE GENE-THERAPY MODEL OF CANCER-TREATMENT

'Bystander' killing of adjacent wild-type tumor cells was seen when tu mors transduced with the herpes thymidine kinase gene were treated wit h the antiviral agent ganciclovir (GCV). Some tumors were 'bystander-r esistant'. Mixtures of different 'sensitive' tumor lines showed cross- transfer of bystander killing, while in mixtures of 'resistant' with ' sensitive' tumors, the resistant phenotype was predominant. Using H-GC V with 'sensitive' mixtures, phosphorylated H-3-GCV was found in both herpes thymidine kinase transduced and unmodified cells, while 'resist ant' cell combinations showed little or no transfer of phosphorylated GCV between cells. The capacity of intracellularly produced nucleotide toxin to spread from cell to cell within a tumor mass effectively amp lifies the apparent efficiency of gene transfer in the tumor and makes feasible the use of this system for therapy of localized cancer.