UP-REGULATION BY AMMONIUM TRICHLORO(DIOXOETHYLENE-0,0')TELLURATE (AS101) OF FAS APO-1 EXPRESSION ON B16 MELANOMA-CELLS - IMPLICATIONS FOR THE ANTITUMOR EFFECTS OF AS101/

It was recently reported that human and mouse melanoma cells express F as ligand (FasL) but almost no Fas, which may contribute to their immu ne privilege. AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate), a synthetic immunomodulator with minimal toxicity, was found to have antitumor effects in various tumor models. Our present study shows tha t AS101 has direct and indirect effects on tumor cells; AS101 inhibits the clonogenicity of B16 melanoma cells in vitro, Moreover, wild-type P53 expression, which is required for induction of Apo-1 expression, increased significantly in AS101-treated cells. We therefore investiga ted Fas expression in AS101-treated B16 cells and found that Fas, but not FasL, expression was significantly increased; moreover, Las recept ors were functional. Longer incubation with AS101 resulted in spontane ous apoptosis triggered by the Fas-FasL system. To explore the relatio nship of these results to the antitumor effects of AS101, we injected B16-F10 mouse melanoma cells into syngeneic C57BL/6 mice carrying the lpr mutation in the Las gene and to gld mutant mice that lack function al Fast. Tumor development in control groups was lowest in the lpr mic e, while no difference was observed between gld and wild-type mice. Am ong the AS101-treated groups, the most pronounced effect appeared in t he lpr mice, while the lowest was seen in the gld mutant mice. Our stu dy suggests that AS101 may render melanoma tumor cells more sensitive to Fas/FasL-induced apoptosis and may therefore have clinical potentia l.