Sequential histopathological changes in vivo after suicide gene therapy ofgastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats

Gastrointestinal cancer is the most important clinical target of gene thera py. Suicide gene therapy, such as with the herpes simplex virus type 1 thym idine kinase (HSV-TK) gene, has been shown to exert antitumor efficacy in v arious cancer models in vitro. We previously reported in situ gene transfer and gene therapy for gastric cancer induced by N-ethyl-N ' -nitro-N-nitros oguanidine (ENNG) in dogs. Here, we describe the sequential histopathologic al changes after suicide gene therapy of N-methgl-N ' -nitro-N-nitrosoguani dine (MNNG)-induced gastric cancer in rats. Gastric tumors were induced by MNNG in 38/73 (52%) of Wistar strain rats. The suicide gene therapy group ( 14 rats) was subjected to in situ gene transfer with a recombinant adenovir us vector carrying the HSV-TK gene driven by CAG promoter (Ad.CAGHSV-TK) in gastric tumor, followed by the antiviral drug ganciclovir (GCV), To observ e the histopathological changes at various times after HSV-TK/GCV gene ther apy, groups of animals were sacrificed at 3, 8, and 30 days after gene tran sfer Apoptosis in the gastric tumors was detected by the TUNEL method to as sess the efficacy of HSV-TK/GCV gene therapy, and it was marked in the 8- a nd 30-day treatment groups compared to the sham operation controls (P < 0.0 01). Various histopathological changes, degeneration of cancer tissue and F ibrosis after necrosis and apoptosis were significantly greater in the 30-d ay treatment group, The HSV-TK gene was detectable in peripheral blood by P CR until 30 days after gene transfer. These results may be useful in devisi ng a method of suicide gene therapy for humans.