Recent reports indicating that tumor necrosis factor-alpha (TNF-alpha) can augment the lethal effects of radiation against certain tumor cell lines prompted us to investigate whether this premise holds true for human colon tumor xenotransplants. Nude mice implanted s.c. with LS174T adenocarcinoma cells (day 0) were randomized into 4 groups: 1) no treatment; 2) TNF-alpha at 1 x 10(4) units/i.v. injection on days 1, 4, 8, and 10; 3) radiation at 4 Gy delivered on days 2, 5, 9, and 11; and 4) TNF-alpha + radiation administered using the same time-dose schedules as for groups 2 and 3. A decrease in tumor growth was obtained with radiation, but not TNF-alpha, as a single modality. However, significanty slower tumor growth was observed with TNF-alpha + radiation when compared to radiation alone. Blood and spleen cells from animals receiving both modalities exhibited the highest oxidative burst capacity. Histopathological evaluation showed large areas of necrosis in animals treated with radiation and with combined radiation + TNF-alpha, and only small areas of necrosis in animals treated with TNF-alpha alone. Necrosis in TNF-alpha-treated animals was not significantly larger than in controls. Irradiation of LS174T cells in culture generally decreased soluble TNF-alpha receptor and carcinoembryonic antigen in cell supernatants, but TNF-alpha was not detectable, regardless of radiation. The results show that pretreatment with TNF-alpha can significantly enhance the effects of radiation against human colon tumor xenografts and that the mechanisms of action may be related to increased oxygen radical production when both agents are administered and/or to induction of apoptosis by TNF-alpha. This data provides support for further investigations using TNF-alpha as an adjunctive agent in the radiotherapy of colon and other cancers.