POTENTIATION OF ANTITUMOR EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA BY MACROPHAGE-COLONY-STIMULATING FACTOR IN A MMB16 MELANOMA MODEL IN MICE

The efficacy of systemic infusion of recombinant human macrophage-colo ny-stimulating factor (M-CSF) in combination with local treatment with human recombinant tumor necrosis factor (TNF) alpha and mouse recombi nant interferon (IFN) gamma was studied in vivo on a subclone of B16 m elanoma (MmB16) in mice. Short-term intravenous administration of M-CS F at a dose of 10(6) units daily had no antitumor effect in vivo. Simi larly, local treatment of tumor with TNF alpha (5 mu g daily) did not produce any therapeutic effect. However, simultaneous administration o f the same dose of TNF alpha with IFN gamma (1000 units daily) resulte d in a synergistic effects manifested by the retardation of tumor grow th. Addition of systemic infusion of M-CSF to the local therapy with T NF alpha and IFN gamma induced further augmentation of antitumor effic acy and delayed progression of MmB16 melanoma. The strengthened antitu mor effect of combination therapy including M-CSF, TNF alpha and IFN g amma was most probably due to the increased release of monocytes from the bone marrow, their recruitment into the site of tumor growth and s ubsequent local stimulation of their antitumor activity.