BYSTANDER TUMORICIDAL EFFECT AND GAP JUNCTIONAL COMMUNICATION IN LUNG-CANCER CELL-LINES

Tumor cells expressing the herpes simplex virus-thymidine kinase (HSV- tk) gene become sensitive to ganciclovir (GCV), and the phenomenon by which tumor cells surrounding the HSV-tk expressing cells also become sensitive to CCV is known as the ''bystander effect.'' The purpose of this study was to investigate the bystander effect in human lung-cance r cell lines, and the role of gap-junctional intercellular communicati on as the mechanism responsible for it. Gap-junctional intercellular c ommunication was measured both with a dye-transfer assay involving sin gle-cell microinjection of Lucifer Yellow and with a PKH26/calcein-AM double-dye-transfer assay. Significant bystander tumoricidal effect wa s observed in lung-cancer cell lines when cultured cells contained onl y 10% HSV-tk expressing cells. This was also observed to occur with ce ll lines of different origin or from different species. Although gap-j unctional intercellular communication characterized by rapid transfer of Lucifer Yellow was not observed, we did detect gap-junctional commu nication marked by the slow transfer of calcein-AM in lung-cancer cell lines. However, neither an inhibitor (I-octanol) nor an enhancer (all trans-retinoic acid [ATRA]) of gap-junctional communication affected the extent of the bystander effect. These findings suggest that low le vels of gap-junctional communication may be efficient for producing th e bystander effect in lung-cancer cells, or chat other mechanisms may underlie this effect. Although gap-junctional communication may play a n important role in generating the bystander effect in tumor cells exp ressing the HSV-tk gene, further knowledge of the mechanism of this ef fect may help improve the treatment of lung cancer with an HSV-tk syst em.