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Potentiation of the Cytocidal Effect of Human Immune Interferon by Different Synthetic Double-Stranded RNAs in the Refractory Human Colon Carcinoma Cell Line BE

Laboratory of Biological Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892

A human cell line BE, derived from an undifferentiated carcinoma of the colon, was studied for its response to the cytocidal effects of human immune interferon (IFN-) alone and in combination with various double-stranded RNAs (dsRNAs). BE cells were moderately refractory to 3-day treatment with IFN- (10 to 300 units/ml) where only 5 to 30% reduction in colony formation occurred. A similar exposure interval to polyriboinosinic·polyribocytidylic acid [poly(I)·poly(C)] (100 µg/ml) had no detectable effect on colony formation. In contrast, the lethal effect of the combination of IFN- and poly(I)·poly(C) was synergistic and this regimen produced a 40 to 80% reduction in colony formation. The cytocidal effects of the combination of IFN- with varying concentrations of the dsRNAs poly(I)·poly(C), polyriboadenylic·polyribouridylic acid [poly(A)·poly(U)], polyriboinosinic·polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(ICLC)], and mismatched dsRNA [rI_m·r(C₁₃, U)_m] were also examined. The concentration of the dsRNAs producing a 50% decrease in cell viability in combination with IFN- (100 units/ml) was 6 µg/ml for poly(I)·poly(C), 1 µg/ml for poly(A)·poly(U), 3 ng/ml for poly(ICLC), and 16 µg/ml for rI_m·r(C₁₃,U)_m-DNA, RNA, and protein synthesis in IFN- and poly(I)·poly(C)-treated cells were reduced in a dose-dependent manner. However, there were no changes in either (2',5')oligoadenylate concentrations or in ribosomal RNA transcription following treatment with IFN- and poly(I)·poly(C). Thus, the synergism resulting from the combination of IFN- and dsRNA appears to be mediated via another, as yet unknown, mechanism.

¹ To whom requests for reprints should be addressed, at National Cancer Institute, Building 37, Room 5D02, Bethesda, MD 20892.

Received 10/ 2/85. Revised 12/ 9/85. Accepted 1/ 3/86.