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Annals of Surgical Oncology 10:305-313 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

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

Michael Duff, AFRCSI, Philip P. Stapleton, PhD, Juan R. Mestre, MD, Sirish Maddali, MD, Gordon P. Smyth, FRCSI, Zhaoping Yan, MD, Tracy A. Freeman, BA and John M. Daly, MD, FACS

From the Weill Medical College of Cornell University/New York Presbyterian Hospital, Department of Surgery, New York, New York.

Correspondence: Address correspondence and reprint requests to: Philip P. Stapleton, PhD, Departments of Surgery and Microbiology/Immunology, Temple University School of Medicine, 3400 North Broad St., Room 513 OMS, Philadelphia, PA 19140; Fax: 215-707-8820; E-mail: ppstap{at}temple.edu

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 µM 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.

Key Words: Melanoma • COX-2 • Macrophage • Interferon {gamma} • Nitric oxide • NS-398




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