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

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.

Low natural cytotoxicity of peripheral blood mononuclear cells in individuals with high familial incidences of cancer.

The possible role that natural cell-mediated cytotoxicity may play as a host defense mechanism against malignant tumors was investigated. We measured natural cell-mediated cytotoxicity (51Chromium released) in 79 normal individuals using K562 leukemia cells as targets in quadruplicate assays after 3, 4, and 5 hr of incubation using three different effector:target cell ratios (6.2:1, 25:1, and 50:1). Natural cell-mediated cytotoxicity was significantly lower (p less than 0.005) in each of the nine separate assay conditions for individuals with a high familial incidence of cancer compared to individuals with a low incidence of cancer. Moreover, natural cell-mediated cytotoxicity inversely correlated with the number of family members with cancer. The relationship between high familial cancer incidence and low natural cell-mediated cytotoxicity was observed in males as well as in females and in nonsmokers as well as in smokers. The same conclusion was reached whether the data were expressed as percentage of 51Chromium released, as lytic units per 10(7) mononuclear cells, or as lytic units per ml of peripheral blood. Thus, defects in natural cell-mediated cytotoxicity may play a role in the initial stages of human tumorigenesis. It may also be possible to identify individuals at increased risk of cancer development.