OBJECTIVE: MegaFas Ligand (MFL) is a recombinant molecule that efficiently triggers apoptosis after binding to the Fas receptor expressed on target cells. The purpose of this study was to determine the potency of MFL in vitro and efficacy in vivo for intraperitoneal treatment of mice implanted with human ovarian carcinoma cells. METHODS: The potency of MFL was compared to that of other Fas agonists in a cytotoxicity assay on SKOV-3 cells. The potency of MFL was further determined by measuring apoptosis in combination with cisplatin. The efficacy of MFL was determined in vivo using peritoneal xenograft models of human ovarian carcinoma. RESULTS: In vitro, MFL induced significantly higher levels of apoptosis than other Fas agonists, and was able to overcome the resistance of the ovarian cancer cell line SKOV-3 to Fas agonist antibody. MFL exerted an enhanced cytotoxic effect when combined with platinum-based drugs, leading to significantly more apoptosis than by incubation with MFL or these drugs alone. Treatment of mice xenografted with SKOV-3 and HOC79 ovarian tumors by intraperitoneal administration of MFL alone or in combination with cisplatin resulted in a significant decrease in peritoneal tumor nodules and ascitic cells, and prolongation of survival as compared to non-treated mice. The beneficial effects of MFL treatment occurred in the absence of severe toxicity. CONCLUSION: MFL is a novel pro-apoptotic molecule that is able to efficiently induce apoptosis in ovarian cancer cells as well as to potentiate the activity of chemotherapeutic agents in vitro and in vivo.