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By J. Thomas August (Eds.)

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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. In the second study, a phosphorothioate oligonucleotide antisense to the protooncogene myb inhibited the growth of human melanoma in mice.

1991; S . T. , 1993). The pattern of metabolites suggests primarily exonuclease activity with perhaps modest contributions by endonucleases. However, a number of lines of evidence suggest that, in many cells and tissues, endonucleases play an important role in the metabolism of oligonucleotides. , 1995). Thus, strategies in which oligonucleotides are modified at only the 3’ and 5’ terminus as a means of enhancing stability have not proved to be successful. 2. In Vitro Cellular Uptake Phosphorothioate oligonucleotides are taken up by a wide range of cells in vitro (R.

1995) Intravenous Mouse Mouse Duck Kulka et al. (1989) Vlassov (1989) Offensperger et al. , 1996). 6 mg/kg/day. A large number of control oligonucleotides failed to show activity. In a similar series of studies, Monia et al. (1996a,b) demonstrated highly specific loss of human c-raf kinase RNA in human tumor xenografts and antitumor activity that correlated with the loss of RNA. Moreover, a series of control oligonucleotides with one to seven mismatches showed decreasing potency in vitro and precisely the same rank-order potencies in vivo.

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