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Titolo:
Pseudo-cyclic oligonucleotides: In vitro and in vivo properties
Autore:
Jiang, ZW; Kandimalla, ER; Zhao, QY; Shen, LX; DeLuca, A; Normano, N; Ruskowski, M; Agrawal, S;
Indirizzi:
Hybridon Inc, Milford, MA 01757 USA Hybridon Inc Milford MA USA 01757Hybridon Inc, Milford, MA 01757 USA ITN Fdn, Oncol Sperimentale D, Naples, Italy ITN Fdn Naples ItalyITN Fdn, Oncol Sperimentale D, Naples, Italy Univ Massachusetts, Med Ctr, Dept Nucl Med, Worcester, MA 01655 USA Univ Massachusetts Worcester MA USA 01655 cl Med, Worcester, MA 01655 USA
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 12, volume: 7, anno: 1999,
pagine: 2727 - 2735
SICI:
0968-0896(199912)7:12<2727:POIVAI>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-A; MIXED-BACKBONE OLIGONUCLEOTIDES; IN-VIVO; ANTISENSE OLIGONUCLEOTIDES; OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE; TISSUE DISTRIBUTION; CYNOMOLGUS MONKEYS; GENE-EXPRESSION; GROWTH-FACTOR; CANCER CELLS;
Keywords:
antisense; in vivo stability; oligonucleotides; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Agrawal, S Hybridon Inc, 155 Fortune Blvd, Milford, MA 01757 USA Hybridon Inc 155 Fortune Blvd Milford MA USA 01757 MA 01757 USA
Citazione:
Z.W. Jiang et al., "Pseudo-cyclic oligonucleotides: In vitro and in vivo properties", BIO MED CH, 7(12), 1999, pp. 2727-2735

Abstract

We have designed and studied antisense oligodeoxynucleotides (oligonucleotides; oligos) which we call 'pseudo-cyclic oligonucleotides' (PCOs). PCOs contain two oligonucleotide segments attached through their 3'-3'- or 5'-5'-ends. One of the segments of the PCO is an antisense oligo complementary toa target mRNA, and the other is a short protective oligo that is 5-8 nucleotides long and complementary to the 3'- or 5'-end of the antisense oligo. As a result of complementarity between the antisense and protective oligo segments, PCOs form intramolecular pseudo-cyclic structures in the absence of the target RNA. The antisense oligo segment of PCOs used for the studies described here is complementary to an 18-nucleotide-long site on the mRNA of the protein kinase A regulatory subunit RI alpha (PKA-RI alpha). Thermal melting studies of PCOs in the absence and presence of the complementary RNA suggest that the pseudo-cyclic structures formed in the absence of the target RNA dissociate, bind to the target RNA, and form heteroduplexes. The results of RNase H cleavage assays suggest that PCOs bind to complementary RNA and activate RNase H in a manner similar to that of an 18-mer conventional antisense PS-oligo. In snake venom (a 3'-exonuclease) or spleen (a 5'-exonuclease) phosphodiesterase digestion studies, PCOs are more stable than conventional antisense oligos because of the presence of 3'-3'- or 5'-5'-linkages and the formation of intramolecular pseudo-cyclic structures. PCOs with a phosphorothioate antisense oligo segment inhibited cell growth of MDA-MB-468 and GEO cancer cell lines similar to that of the conventional antisense PS-oligo, suggesting efficient cellular uptake and target binding. The nuclease stability studies in mice suggest that PCOs have higher in vivo stability than antisense PS-oligos. The studies in mice showed similar pharmacokinetic and tissue distribution profiles for PCOs to those of antisense PS-oligos in general, but rapid elimination from selected tissues. (C) 1999 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/09/20 alle ore 09:29:18