AUGMENTATION OF ANTITUMOR EFFICACY BY THE COMBINATION OF ACTINOMYCIN-D WITH TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA ON A MELANOMA MODEL IN MICE

The efficacy of combination treatment with actinomycin D (Act D), reco mbinant human tumor necrosis factor-alpha (TNF-alpha), and recombinant murine interferon-gamma (IFN-gamma) was examined on established MmB16 melanoma in mice. TNF-alpha alone had marginal effect in vitro on mel anoma cells. However, when this cytokine was combined with either Act D or IFN-gamma, synergistic cytostatic/cytotoxic effects were observed . The highest cytotoxicity was demonstrated in cultures of melanoma ce lls in which all three agents together were added. In mice inoculated with 10(6) melanoma cells (into the footpad of the hind limb) and trea ted locally with Act D, TNF-alpha and IFN-gamma, beneficial therapeuti c effects were found. When initiated 1 week after tumor cell inoculati on, the 7-day treatment with all these agents administered together at daily doses: 0.2 mu g (Act D), 1 mu g (TNF-alpha), and 200 U (IFN-gam ma) resulted in a significant delay of tumor progression in comparison to the therapy that included either Act D alone or TNF-alpha in combi nation with IFN-gamma. Side effects of such a treatment, both local an d systemic, were negligible. The results of this study demonstrate tha t combination of regional chemotherapy (actinomycin D) and immunothera py (TNF-alpha/IFN-gamma) may display higher efficacy than either treat ment alone and may increase therapeutic index without augmenting toxic effects.