ENHANCED ANTITUMOR EFFICACY IN MICE BY COMBINATION TREATMENT WITH INTERLEUKIN-1-ALPHA AND INTERFERON-ALPHA

The antitumor efficacy of recombinant murine interleukin-1 alpha (rMuI L-1 alpha) was evaluated either alone or in combination with recombina nt human hybrid interferon alpha A/D (IFN-alpha A/D) against the murin e B16F10 malignant melanoma. Treatment of subcutaneous tumor-bearing m ice intraperitoneally with rMIL-1 alpha resulted in a dose-dependent i nhibition of tumor growth with the greatest activity obtained with the maximum tolerated dose of rMuIL-1 alpha (10 mu g per treatment). Augm ented tumor inhibition comparable to that seen in mice treated with a high dose of rMuIL-1 alpha was observed in subcutaneous tumor-bearing mice injected with the combination of IFN-alpha A/D and a low dose of rMuIL-1 alpha. Similar inhibition of subcutaneous tumor growth was obt ained in T-cell-deficient nude or natural killer cell-deficient beige mice. In contrast, treatment of mice bearing B16F10 experimental pulmo nary metastases with rMuIL-1 alpha resulted in no decrease in the numb er of metastases, and rMuIL-1 alpha did not potentiate the antimetasta tic activity of IFN-alpha A/D. A synergistic induction of IL-6 was ind uced in mice treated with the combination of rMuIL-1 alpha plus IFN-al pha A/D but the level of IL-6 induced was not correlated with inhibiti on of tumor growth because this elevation of IL-6 was not observed in tumor-bearing nude mice. No direct antiproliferative activity was demo nstrable in vitro against B16F10 cells with rMuIL-1 alpha, IL-6, or rM uIL-1 alpha plus IL-6, and addition of these cytokines did not enhance the antiproliferative activity of IFN-alpha A/D, These results indica te that after parenteral administration the combination of rMuIL-1 alp ha plus IFN-alpha A/D has enhanced antitumor efficacy relative to eith er cytokine alone.