Advances in Pharmacology by J. Thomas August (Eds.)

By J. Thomas August (Eds.)

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Expression of interleukin 1 in mice was inhibited by systemic administration of antisense oligonucleotides (Burch and Mahan, 1991). , 1992). , 1993). Several reports further extend the studies of phosphorothioate oligonucleotides as antitumor agents in mice. In one study, a phosphorothioate oligonucleotide directed to inhibition of the bcr-abl oncogene was administered at a dose of 1 mg/day for 9 days intravenously to immunodeficient mice injected with human leukemic cells. , 1994). However, it is possible that the effects on the RNA levels were secondary to effects on the growth of various cell types.

1994) Woodburn et al. (1994) Kindy (1994) Konradi et al. (1994) Lai et al. (1994) Mani et al. (1994) McCarthy et al. (1994) McCarthy et al. (1994) continues Pharmacology of Antisense Oligonucleotides 25 TABLE I (Continued) Target Route Species Ref AT1-angiotensin receptor Tryptophan hydroxylase AT1 -angiotensin receptor CRH,-corticotropin-releasing hormone receptor 6 opioid receptor S opioid receptor Oxytocin Oxytocin Substance P receptor Tyrosine hydroxylase c-jun D1 doparnine receptor Dz doparnine receptor D2 dopamine receptor D2 dopamine receptor Viral models HSV-1 Tick-borne encephalitis Duck hepatitis virus Intracerebral In tracere bra1 Intracerebral lntracerebral Rat Mouse Rat Rat Sakai et al.

1991). , 1991; S . T. , 1995). Again, the oligonucleotides appear to be competitive antagonists for the DNA-RNA substrate. , 1991). , 1991; S. T. , 1995). In our laboratories, we have shown extensions of 2-3 nucleotides only. At present, a full explanation as to why no longer extensions are observed is not available. , 1991). , 1991), and to protein kinase C. Various viral polymerases have also been shown to be inhibited by phosphorothioates (for review, see Stein and Cheng, 1993). In addition, we have shown potent, non-sequence-specific inhibition of RNA splicing by phosphorothioates (Hodges and Crooke, 1995).

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