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Effects of Fibroblast and Recombinant Leukocyte Interferons and Double-Stranded RNA on ppp(2'–5')A_n Synthesis and Cell Proliferation in Human Colon Carcinoma Cells in Vitro

Applied Pharmacology Section, Laboratory of Medicinal Chemistry and Pharmacology, National Cancer Institute, Bethesda, Maryland 20205

The antiproliferative effect of human fibroblast interferon (IFN-ß), human recombinant leukocyte interferon (IFN-A), and polyinosinic·polycytidylic acid [poly(I)·poly(C)] was investigated in human colon carcinoma cell line HT-29. Exposure of HT-29 cells for 1 to 3 days with 100 to 2000 units of either interferon preparation resulted in a 30 to 50% inhibition of growth after 3 days. Similar treatment of cells with 100 µg per ml poly(I)·poly(C) resulted in progressive inhibition of growth by 50 to 60% in 2 to 3 days. The inhibitory effects of combination of either IFN-ß or IFN-A with poly(I)·poly(C) were additive with up to 80 to 90% inhibition of cell growth after 3 days of exposure. None of the treatment regimens was markedly cytocidal, and only 25 to 30% reduction in colony formation was noted under optimal treatment conditions following 2 to 3 days of drug exposure. Measurements of DNA, RNA, and protein synthesis following interferon treatment indicated a dose-dependent reduction in all three parameters, particularly when interferon was administered with poly(I)·poly(C). The associated changes in the (2',5')oligoadenylate [(2',5')oligo(A)] pathway produced by IFN-ß and IFL-A were measured under growth-inhibitory conditions. A concentration-dependent induction of (2',5')oligo(A) synthetase was produced by IFN-ß or IFL-A with a concomitant decrease in (2',5')oligo(A) phosphodiesterase. Poly(I)·poly(C) alone induced (2',5')oligo(A) synthetase activity but had no effect on the associated activity of phosphodiesterase. The combination of either IFN-ß or IFL-A and poly(I)·poly(C) further reduced (2',5')oligo(A) phosphodiesterase activity. There was no general dose-response correlation between the induction of (2',5')oligo(A) synthetase and the cytostatic activity of interferon treatment alone or in combination with double-stranded RNA.

¹ To whom requests for reprints should be addressed, at National Cancer Institute, Building 37, Room 6D28, Bethesda, Md. 20205.

Received 8/ 6/82. Accepted 3/ 9/83.

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