Backbone modification alters the efficacy of antisense oligonucleotides directed against mRNA encoding either TGF-alpha or EGFR in the treatment of prostate cancer cell lines.

METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY(2002)

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摘要
Antisense oligonucleotides (oligos) directed against mRNA-encoding, transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR), have been shown to significantly inhibit in vitro and in vivo growth of prostate tumor models. Recently, second generation oligos have been employed with identical base sequences, but containing backbone modifications that enhance stability, solubility, and circulatory patterns. Using relatively low concentrations of oligos, we compared the efficacy of the first generation phosphorothioated oligos against TGF-alpha (MR1) and EGFR (MR2) with second generation oligos containing completely phosphorothioated backbones and different patterns of 2'-methoxyethyl (2'-MOE) backbone modifications, while retaining the original designated base sequence using, the LNCaP and PC-3 prostate cancer cell lines, respectively. All experiments were, conducted in vitro with lipofectin to enhance oligo entry. Under these conditions, using oligo concentrations between 0.83 and 3.32 muM for LNCaP cells treated with oligos directed against TGF-alpha only the first generation MR1 had inhibitor, activity. When treated with oligos directed against EGFR, none of the oligos had inhibitory activity, and they behaved similarly. Using the PC-3 cell line and treatment directed against TGF-alpha with oligo concentrations between 0.42 and 3.32 muM,first generation MR1 aid second generation 5005 behaved similarly, with no notable effect, while second generation 5007 produced dramatic growth stimulation. When PC-3 cells were treated with oligos directed against EGFR, second generation 5006 and 5008 had similar and apparently dose-dependent inhibition. We conclude that backbone modifications influence oligo efficacy and may result hi either enhanced or diminished activity Because of their activity, against the hormone insensitive PC-3 cells, the 5006 and 5008 compounds warrant additional study at greater concentrations and also merit in vivo testing. (C) 2002 Prous Science. All rights reserved.
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关键词
antisense oligonucleotides,prostate cancer,TGF-alpha,EGFR
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