Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon gamma.

Abstract

Melanoma inhibits macrophage tumoricidal activity and increases the expression of cyclooxygenase-2 (COX-2). In this study, we sought to determine whether inhibition of COX-2 could restore macrophage function and hence maximize the antitumor activity of the immune stimulant interferon gamma (IFN gamma). Peritoneal macrophages were exposed to B16 melanoma-conditioned medium for 24 hours with or without the COX-2 inhibitor NS-398 and then were stimulated with lipopolysaccharide and IFN gamma. Cytotoxic activity, nitrite production, and cytokine production by the stimulated macrophages were measured. In addition, B16 melanoma cells were implanted intradermally into mice treated with IFN gamma (14,000 U on alternate days) alone or with a combination of IFN gamma and a COX-2 inhibitor (NS-398 or nimesulide). Mice were assessed for tumor growth and survival. Macrophage cytotoxicity and nitrite production were significantly suppressed by melanoma-conditioned medium (P <.01). This was prevented by 200 micro M of NS-398 (P <.05). In vivo, combined treatment with IFN gamma and a COX-2 inhibitor caused a significant inhibition of tumor growth (P <.01) and improved survival (P =.02) compared with controls. COX-2 inhibition reversed melanoma-induced suppression of macrophage function, and combined treatment of IFN gamma plus a COX-2 inhibitor was maximally effective in reducing tumor growth and improving survival.