title: Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon gamma.
abstract: 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 gamma (IFN gamma).
  
  
  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 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Weill Medical College of Cornell University/New York Presbyterian Hospital, Department of Surgery, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Duff
authors.forename: Philip P
authors.initials: PP
authors.lastname: Stapleton
authors.forename: Juan R
authors.initials: JR
authors.lastname: Mestre
authors.forename: Sirish
authors.initials: S
authors.lastname: Maddali
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Smyth
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Yan
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Freeman
authors.forename: John M
authors.initials: JM
authors.lastname: Daly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology*; D007527:Isoenzymes / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013534:Survival; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases