Cellular and enzymatic activities of a synthetic heteropolymer double-stranded RNA of defined size.
We have synthesized a novel heteropolymer double-stranded RNA (dsRNA) molecule of defined length and strandedness (dsRNA309) and evaluated its ability to induce cytokine gene expression, activate dsRNA-dependent enzymes, and inhibit both tumor cell growth and virus replication. Unlike the conventionally studied synthetic homopolymer dsRNAs, polyinosinic acid:polycytidylic acid (poly(I-C)) and its mismatched analogue polyinosinic:polycytidylic, uridylic acid (poly(I-C12,U), dsRNA309 possessed restricted biological activity. dsRNA309 was unable to inhibit tumor cell growth or efficiently induce cytokine (i.e. interferon-beta and interleukin-1 alpha) gene expression. However, dsRNA309 was able to inhibit virus replication and activate dsRNA-dependent intracellular enzymes, 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and the dsRNA-activated inhibitor kinase in in vitro assay systems. Overall, dsRNA309 provided a means for examining the mechanisms governing the dsRNA-regulated antiviral and antiproliferative responses, and studies with dsRNA309 demonstrated that the ability of a synthetic dsRNA to activate dsRNA-dependent intracellular enzymes does not necessarily predict the same gene inducing capacity.
Haines
D S
DS
Department of Neoplastic Diseases, Hahnemann University, Philadelphia, Pennsylvania 19102.
Suhadolnik
R J
RJ
Hubbell
H R
HR
Gillespie
D H
DH
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D010584:Bacteriophage phi X 174; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D010957:Plasmids; D011070:Poly I-C / Q000378:metabolism; D011072:Poly U / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase
D007375:Interleukin-1; D012330:RNA, Double-Stranded; D011072:Poly U; D016899:Interferon-beta; C047490:poly(I).poly(c12,U); D011494:Protein Kinases; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D011070:Poly I-C