We examined whether 5-fluorouracil (5-FU) induces nitric oxide (NO) production and evaluated the role of NO in antitumor activity in human gastric cancer cells. MKN-1 gastric cancer cells were treated with the IC50 of 5-FU in the presence of interferon-γ (IFN-γ). In addition, s-methylisothiourea (an antagonist of inducible nitric oxide synthase) or anti-TNF-α antibody was added to the culture medium. Production of NO was measured by nitrite assay, TNF-α was measured by enzyme-linked immunoabsorbent assay, antitumor activity was evaluated by 3-[4,5-dimethylethiazol-2-yl]-2,5-dipheniltetrasolium bromide (MTT) assay. After 5-FU treatment in the presence of IFN-γ, NO and TNF-α were produced and anti-tumor activity was enhanced. In contrast, s-methylisothiourea abolished the antitumor activity of 5-FU treatment. Anti-TNF-α antibody inhibited NO production and decreased the antitumor activity. 5-FU induces NO production by gastric cancer cells, and NO participates in antitumor activity in gastric cancer cells. These effects may be mediated by TNF-α production.

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