Effects of fibroblast and recombinant leukocyte interferons and double-stranded RNA on ppp(2'-5')An synthesis and cell proliferation in human colon carcinoma cells in vitro.
The antiproliferative effect of human fibroblast interferon (IFN-beta), human recombinant leukocyte interferon (IFN-alpha 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 micrograms 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-beta or IFN-alpha 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-beta and IFL-alpha A were measured under growth-inhibitory conditions. A concentration-dependent induction of (2',5')oligo(A) synthetase was produced by IFN-beta or IFL-alpha 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-beta or IFL-alpha 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.
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000227:Adenine Nucleotides / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D009841:Oligonucleotides / Q000096:biosynthesis*; D009843:Oligoribonucleotides / Q000096:biosynthesis*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D012330:RNA, Double-Stranded / Q000494:pharmacology*
D000227:Adenine Nucleotides; D007370:Interferon Type I; D009841:Oligonucleotides; D009843:Oligoribonucleotides; D012330:RNA, Double-Stranded; C023505:2',5'-oligoadenylate; D012313:RNA; D015088:2',5'-Oligoadenylate Synthetase; D010727:Phosphoric Diester Hydrolases; D011070:Poly I-C