Hyperstabilization of sense-antisense duplexes and inhibition of translation (Meeting abstract).

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Hyperstabilization of sense-antisense duplexes and inhibition of translation (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A1835 1994. Unique Identifier : AIDSLINE ICDB/94603521
Kim DY; Shih DS; Cho DY; Swenson DH; School of Veterinary Medicine, Louisiana State University, Baton; Rouge, LA 70803

Abstract: The antitumor agents CC-1065 and U-71,184 raise the Tm of double-stranded DNA. We undertook this study to determine if these agents could hyperstabilize RNA-DNA (sense-antisense) duplexes or DNA duplexes in which one strand contained phosphorothioate (PS) or methylphosphonate (MP) internucleotide linkages. Sequences 1 and 2 (5'-TTACTTCAGTTATCAGACCA-3'; CC-1065 target underlined) were from the env gene of equine infectious anemia virus (EIAV). Seq 1 was DNA and seq 2 was RNA. Antisense seq 3, 4 and 5 were complementary to seqs 1 and 2 and were comprised of phosphodiester (PO), PS and MP, resp. Duplexes from seq1-seq3, seq1-seq4, seq1-seq5 all bound CC-1065 and showed elevations in Tm of 17 to 21 C. Poly(rA)-oligo(dT20) and oligo(dA20)-oligo(dT20) showed increases in Tm of 28 and 31 C, resp, when bound to CC-1065. Seq2-seq3 and seq2-seq4 each bound 1 CC-1065/duplex, but insufficient material was available to evaluate Tm. U-71,184 caused strong elevation of Tm (greater than 15 C) only with seq1-seq5 and oligo(dA20)-oligo(dT20). An mRNA transcript (585-mer) of EIAV was targeted approx 200 bases downstream from the initiation site with a 20-mer PO antisense oligonucleotide. Translation (wheat germ extract) was inhibited in a dose-dependent fashion at antisense:mRNA ratios ranging from 10 to 72, and concomitant incubations of the duplexes with CC-1065 (4x compared to antisense) caused significant enhanced depression of translation for the higher doses. A 20-mer sense sequence, incubated with the MRNA, with and without CC-1065, had little or no effect on translation. Antisense oligonucleotides tethered to CC-1065-like ligands may yield duplexes with MRNA of high stability.

Keywords: Base Sequence *Genes, env Infectious Anemia Virus, Equine/*GENETICS Molecular Sequence Data Oligodeoxyribonucleotides/*TOXICITY Oligonucleotides, Antisense/*TOXICITY RNA, Messenger/BIOSYNTHESIS Transcription, Genetic Translation, Genetic/*DRUG EFFECTS Wheat/METABOLISM ABSTRACT
941230
M94C4328

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