EVALUATION OF THE BYSTANDER EFFECT IN EXPERIMENTAL BRAIN-TUMORS BEARING HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE BY SERIAL MAGNETIC-RESONANCE-IMAGING

Antitumor effects of herpes simplex virus-thymidine kinase (HSV-tk) ge ne transfer followed by ganciclovir (GCV) administration were studied by serial magnetic resonance imaging (MRI) with reference to the bysta nder effect. Mixed populations of 9L-gliosarcoma cells transduced with the HSV-tk gene (TK cells) and wild-type 9L cells were implanted into the brain of syngeneic Fisher rats at various ratios (total cell numb er, 10(5) cells; percentage of TK cells, 100%, 25%, 10%, or 0%). Rats were treated with GCV (30 mg/kg per day) or saline for 14 days and tum or masses were visually monitored using MRI. All of the saline-treated rats (regardless of TK cell percentage) and GCV-treated rats inoculat ed with 0% TK cells died between day 19 and day 31 (mean survival, 22. 9 days) due to progressive tumor growth. The GCV-treated rats inoculat ed with more than 10% of TK cells lived significantly longer than the saline-treated rats (p < 0.01). The mean survivals of GCV-treated grou ps were 50.7, 70.0, and longer than 100 days for 10%, 25%, and 100% TK cells, respectively. MRI study revealed that reduction in tumor size and disappearance of tumor were observed in the GCV-treated rats inocu lated with 10% or 25% TK cells. Complete regression of the tumor was, however, observed only in the rats implanted with 100% TK cells. The p resent results show that the bystander effect is clearly observed in v ivo in a TK percentage-dependent manner, and a population of more than 25% of TK-positive cells is required for complete tumor elimination.