Augmented antitumor effect of combined human natural interferon-alpha and mismatched double-stranded RNA treatment against a human malignant melanoma xenograft

Abstract

The antitumor effect of combined natural human interferon-alpha (IFN) and mismatched double-stranded RNA (dsRNA) treatment against the human malignant melanoma cell line, BRO, was studied. In vitro results, using a tissue culture antiproliferative assay, indicated that these cells were moderately sensitive to IFN-alpha. In contrast, mismatched dsRNA had no antitumor effect, and a minimal stimulation of cell growth, over part of the concentration range tested, was observed. Mismatched dsRNA did not potentiate the antitumor effect of IFN-alpha in cells receiving combination treatment. Xenografts of BRO cells, inoculated subcutaneously into nude mice, were used to evaluate the antitumor effects of IFN-alpha and mismatched dsRNA. Growth of the primary tumor was inhibited by both drugs alone or in combination (p less than 0.001), but the combined treatment was most effective and appeared to be additive. The number of spontaneous lung metastases was also inhibited (p less than 0.02) in all treatment groups. Survival, however, was significantly increased only in the IFN-alpha/mismatched dsRNA group (p less than 0.02 compared to controls, p less than 0.05 compared to mismatched dsRNA alone). Determination of splenic natural killer (NK) cell activity against BRO cells demonstrated that significantly augmented NK activity to the same extent, but that the IFN-alpha alone had no effect. These results indicate that IFN-alpha worked through direct antiproliferative mechanisms while mismatched dsRNA stimulated host immunomodulatory effects. The increased tumor growth inhibition and survival in the dual treatment group appears to result from the combined direct antiproliferative and indirect immunomodulatory effects.