Download PDF by J. Thomas August (Eds.): Advances in Pharmacology

By J. Thomas August (Eds.)

ISBN-10: 0120329417

ISBN-13: 9780120329410

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1994). A number of studies from our laboratories that directly examined target RNA levels, target protein levels, and pharmacological effects using a wide range of control oligonucleotides and examination of the effects on closely related isotypes have been completed. Single and chronic daily administration of a phosphorothioate oligonucleotide designed to inhibit mouse protein kinase C a (PKC-a) selectively inhibited expression of PKC-a RNA in mouse liver without effects on any other isotype.

Polynucleotides and other polyanions have been shown to cause release of cytokines (Colby, 1971). , 1991). , 1992). In the latter study, the oligonucleotides that displayed natural killer (NK) cell-stimulating activity contained specific palindromic sequences and tended to be guanosine rich. Collectively, these observations indicate that nucleic acids may have broad immunostimulatory activity. It has been shown that phosphorothioate oligonucleotides stimulate B lymphocyte proliferation in a mouse splenocyte preparation (analogous t o bacterial DNA) (Psietsky and Reich, 1993), and the response may underlie the observations of lymphoid hyperplasia in the spleen and lymph nodes of rodents caused by repeated administration of these compounds (see Section V,F,3).

The increase in T, value was attributed to ( I ) the hydrophobic nature of the modification, (2) increased stacking interaction, and (3) favorable pK, of the base. In contrast, some C-8-substituted bases have yielded improved nuclease resistance when incorporated in oligonucleotides (Sanghvi, 1993) but seem to be somewhat destabilizing. 3. Oligonucleotide Conjugates Although conjugation of various functionalities to oligonucleotides has been reported to achieve a number of important objectives, the data supporting some of the claims are limited and generalizations are not possible on the basis of the data now available.

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

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