Gonadal tumors of mice double transgenic for inhibin-alpha promoter-driven simian 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 inhibin alpha-subunit promoter/Simian virus 40 T-antigen (Inhalpha/Tag) fusion gene. The mice develop gonadal somatic cell tumors at the age of 5-7 months; the ovarian tumors originate from granulosa cells, and those of the testes from Leydig cells. In the present study another TG mouse line was produced, expressing under the same inh-alpha promoter the herpes simplex virus thymidine kinase gene (Inhalpha/TK). Crossbreeding of the two TG mouse lines resulted in double TG mice (Inhalpha/TK-Inhalpha/Tag), which also developed gonadal tumors. The single (Inhalpha/Tag) and double TG (Inhalpha/TK-Inhalpha/Tag) mice, both bearing gonadal tumors, were treated at the age of 5.5-6.5 months with ganciclovir (GCV, 150 mg/kg body weight twice daily 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 gonads 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 vitro efficacy of ACV and GCV treatments in transiently HSV-TK-transfected KK-1 murine granulosa tumor cells, originating from a single-positive Inhalpha/Tag mouse. GCV proved to be more effective and more specific than ACV in 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.

Human papillomavirus-induced carcinogenesis with p53 deficiency in mouse: novel lymphomagenesis in HPV16E6E7 transgenic mice mimicking p53 defect.

To investigate the transforming activity of human papillomavirus (HPV) E6 and E7 genes in vivo, we previously established transgenic mouse lines containing HPV16E6E7, in which male mice develop a Leydig cell tumors with a very high incidence. Because HPV-induced carcinogenesis is highly related to p53, we changed the dose of p53 gene in the transgenic lines by the mice crossing with p53-disrupted mice. The transgenic mice with homozygous wild-type p53 alleles developed only the testicular tumor, whereas novel T cell lymphomagenesis occurred in the heterozygous p53-disrupted E6E7 (p53+/-E6E7) transgenic mice. In this tumor and even in the normal spleen, the absence of p53 protein was observed, whereas the p53 mRNA was expressed with a normal size, suggesting the degradation of p53 protein in these tissues. These results suggest that HPV16E6 could stimulate p53 protein degradation in mouse cells and induced the lymphomagenesis in a manner indistinguishable from p53 deficiency.