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), recombinant human tumor necrosis factor-α (TNF-α), and recombinant murine interferon-γ (IFN-γ) was examined on established MmB16 melanoma in mice. TNF-α alone had marginal effect in vitro on melanoma cells. However, when this cytokine was combined with either Act D or IFN-γ, synergistic cytostatic/cytotoxic effects were observed. The highest cytotoxicity was demonstrated in cultures of melanoma cells in which all three agents together were added. In mice inoculated with 10⁶ melanoma cells (into the footpad of the hind limb) and treated locally with Act D, TNF-α and IFN-γ, beneficial therapeutic effects were found. When initiated 1 week after tumor cell inoculation, the 7-day treatment with all these agents administered together at daily doses: 0.2 μg (Act D), 1 μg (TNF-α), and 200 U (IFN-γ) resulted in a significant delay of tumor progression in comparison to the therapy that included either Act D alone or TNF-α in combination with IFN-γ. Side effects of such a treatment, both local and systemic, were negligible. The results of this study demonstrate that combination of regional chemotherapy (actinomycin D) and immunotherapy (TNF-α/IFN-γ) may display higher efficacy than either treatment alone and may increase therapeutic index without augmenting toxic effects.