T-cell-immunity-based inhibitory effects of orally administered herbal medicine juzen-taiho-to on the growth of primarily developed melanocytic tumors in RET-transgenic mice

We examined the effect of oral administration of juzen-taiho-to, one of the most popular herbal medicines in Japan, on primary melanocytic tumor growt h in RET-transgenic mice. There was virtually no difference between the len gths of tumor-free stages in the juzen-taiho-to-treated mice and the untrea ted littermate control mice. The rate of tumor growth in the juzen-taiho-to -treated mice, however, was greatly suppressed during the entire period aft er the initial tumor development. Correspondingly, the life span of juzen-t aiho-to-treated transgenic mice was longer (over 6 mo in mean value) than t hat of control mice. We partially elucidated the mechanism of the antitumor effect of juzen-taiho-to. The addition of juzen-taiho-to at any of a wide range (50-1600 mug per nil) of concentrations to in vitro cultures of Mel-R et cells, a malignant melanoma cell line derived from a MET-transgenic mous e, caused neither cell death nor cell cycle arrest directly. The addition o f 50-400 mug per ml of juzen-taiho-to to cultures of murine spleen cells, h owever, promoted their DNA synthesis. More importantly, peritoneal exudate cells from the juzen-taiho-to-treated transgenic mice, in which the ratio a nd number of T cells were increased, displayed an antitumor immunity agains t Mel-Ret cells in vitro. Interestingly, the peritoneal-exudate-cell-associ ated antitumor immunity was further augmented by the addition of 200-400 mu g per ml of juzen-taiho-to in vitro. This immunity, which was primarily con veyed by Thy-1(+) T cells, was antigen (RET/melanoma) specific and cytotoxi c. Amongst various chemical ingredients of jutzen-taiho-to examined in this study, glycirrhizin displayed an action, partially replacing that of jutze n-taiho-to, in promoting anti-Mel-Ret immunity when supplementarily added i n vitro. These results suggest that juzen-taiho-to suppresses once-develope d primary melanocytic tumors through potentiation of T-cell-mediated antitu mor cytotoxic immunity in vivo.