Upregulation by AS101 of FAS (APO-1) expression on b16 melanoma cells: Implications for the antitumor effects of AS101

Malignant melanoma accounts for the rising mortality from skin cancer. Human and mouse melanoma cells have recently been found to express Fas ligand (FasL) but almost no Fas. This may contribute to the immune privilege of these tumors. AS101 has previously been found to have antitumor effects in various murinetumor models. In the present study we show that AS101 may significantly increase Fas expression-of B16F10 melanoma cells without affecting the level of their FasL expression. In addition, a pronounced increase in FasL expression was noted when spleen cells were incubated wth AS101. Ligation of AS101 -pretreated B16 melanoma cells with anti-Fas antibodies resulted in increased early and late apoptosis as compared to untreated cells. In order to explore the implications of these events for the antitumor effects of AS101, we injected B16F10 mouse melanoma cells to syngeneic C57BI/6 mice carrying the Ipr mutation in the Fas gene and to gld mutant mice that lack functional FasL. Tumor progression was compared to that of wild type C57BI/6 mice. AH mice groups were either treated daily with AS101 or with PBS. Tumor progression in Ipr mice injected with PBS was significantly slower than in both wild type and gld mice. This was probably due to the ability of FasL expressing melanoma cells to kill infiltrating immune effector cells in both wild type and gld mice, but not in Ipr mice, through FasLFas interaction. Injection of AS101 resulted in further decrease in tumor size in all groups. The most significant tumor inhibition occurred in the C57BI/6 mice with the mutated Fas gene. These results suggest that pharmacological products such as AS101 that simultaneously upregulate Fas expression on tumor cells and FasL on T cells may render tumor cells more sensitive to FasL-induced killing and thus help to break the immunological unresponsiveness to melanoma. Such products may thus supplement conventional treatments of malignant melanoma.