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Analysis of ribosyl-modified, mixed backbone analogs of a bcl-2/bcl-xL antisense oligonucleotide.

Abstract
Progress in oligonucleotide chemistry has provided second-generation antisense oligonucleotides with increased efficacy and reduced non-antisense-related toxicity. The ability of the 2'-O-(2-methoxyethylribose) (2'-MOE)-modified phosphorothioate gapmer oligonucleotide 4625, which matches the bcl-2 mRNA and has three base-mismatches to bcl-xL, to inhibit bcl-2 and bcl-xL expression and induce tumor cell apoptosis has been described. Here we investigated the consequences of adding of 2'-MOE or 2'-Me modifications to ribonucleotides at either the two ends of the sequence, or the center region together with different combinations of phosphodiester/phosphorothioate backbones on the activity of oligonucleotide 4625. The ability of the various 4625 analogs, including the parental first-generation oligonucleotide 3005, to inhibit bcl-2 and bcl-xL expression, and diminish cell growth or induce tumor cell death was assessed in SW2 lung cancer cells using real-time PCR, Western blotting and cell viability assays. Only oligonucleotide 4625 exhibited a potent bispecific antisense activity against bcl-2 and bcl-xL, which effectively reduced tumor cell viability. The other antisense oligonucleotides were either uniquely active against bcl-2 or completely inactive. Our data suggest that the 2'-MOE modification in combination with the phophorothioate gapmer chemistry is the optimal format of the 4625 sequence in terms of antisense activity and biological efficacy.
AuthorsRobert A Olie, Jonathan Hall, Francois Natt, Rolf A Stahel, Uwe Zangemeister-Wittke
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1576 Issue 1-2 Pg. 101-9 (Jun 07 2002) ISSN: 0006-3002 [Print] Netherlands
PMID12031489 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • oligonucleotide 4625
Topics
  • Apoptosis
  • Carcinoma, Small Cell
  • Cell Division (drug effects)
  • Cell Survival (drug effects)
  • Drug Screening Assays, Antitumor
  • Lung Neoplasms
  • Oligonucleotides (chemistry, pharmacology)
  • Oligonucleotides, Antisense (chemistry, pharmacology)
  • Proto-Oncogene Proteins c-bcl-2 (analysis, biosynthesis)
  • Tumor Cells, Cultured
  • bcl-X Protein

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