Gonadal tumors of mice double transgenic for inhibin-alpha promoter-drivensimian virus 40 T-antigen and herpes simplex virus thymidine kinase are sensitive to ganciclovir treatment

We have previously produced transgenic (TG) mice expressing the mouse inhib in alpha -subunit promoter/Simian virus 40 T-antigen (Inh alpha /Tag) fusio n gene. The mice develop gonadal somatic cell tumors at the age of 5-7 mont hs; the ovarian tumors originate from granulosa cells, and those of the tes tes from Leydig cells. In the present study another TG mouse line was produ ced, expressing under the same inh-alpha promoter the herpes simplex virus thymidine kinase gene (Inh alpha /TK). Crossbreeding of the two TG mouse li nes resulted in double TG mice (Inh alpha /TK-Inh alpha /Tag), which also d eveloped gonadal tumors. The single (Inha/Tag) and double TG (Inh alpha /TK -Inh alpha /Tag) mice, both bearing gonadal turners, were treated at the ag e of 5.5-6.5 months with ganciclovir (GCV, 150 mg/kg body weight twice dail y i.p.) for 14 days, or with aciclovir (ACV, 300-400 mg/kg body weight per day perorally) for 2 months. During GCV treatment, the total gonadal volume including the tumor, decreased in double TG mice by an average of 40% (P < 0.05), while in single TG mice, there was a concomitant increase of 60% in gonadal size (P < 0.05). GCV was also found to increase apoptosis in gonad s of the double TG mice. Peroral treatment with ACV was less effective, it did not reduce significantly the gonadal volume. We also analyzed the in vi tro efficacy of ACV and GCV treatments in transiently HSV-TK-transfected KK -1 murine granulosa tumor cells, originating from a single-positive Inh alp ha /Tag mouse. GCV proved to be more effective and more specific than ACV i n action. These results prove the principle that targeted expression of the HSV-TK gene in gonadal somatic cell tumors is potentially useful for tumor ablation by antiherpes treatment. The findings provide a lead for further development of somatic gene therapy for gonadal tumors.