Cyclooxygenase-2 Inhibition Improves Macrophage Function in Melanoma and Increases the Antineoplastic Activity of Interferon ?

• Published in: Annals of surgical oncology Vol. 10; no. 3; pp. 305 - 313
• Main Authors: Duff, Michael, Stapleton, Philip P., Mestre, Juan R., Maddali, Sirish, Smyth, Gordon P., Yan, Zhaoping, Freeman, Tracy A., Daly, John M.
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01-04-2003
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/ASO.2003.04.033

Background: 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 γ (IFNγ). Methods: 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 IFNγ. 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 IFNγ (14,000 U on alternate days) alone or with a combination of IFNγ and a COX-2 inhibitor (NS-398 or nimesulide). Mice were assessed for tumor growth and survival. Results: Macrophage cytotoxicity and nitrite production were significantly suppressed by melanoma-conditioned medium (P < .01). This was prevented by 200 μM of NS-398 (P < .05). In vivo, combined treatment with IFNγ and a COX-2 inhibitor caused a significant inhibition of tumor growth (P < .01) and improved survival (P = .02) compared with controls. Conclusions: COX-2 inhibition reversed melanoma-induced suppression of macrophage function, and combined treatment of IFNγ plus a COX-2 inhibitor was maximally effective in reducing tumor growth and improving survival.