Circular antisense oligonucleotides inhibit growth of chronic myeloid leukemia cells.

摘要: Antisense represents a conceptually powerful method for regulating gene expression. However, antisense oligonucleotides developed to date manifest two serious limitations—nuclease susceptibility and nonspecific hybridization. Circular may be superior conventional linear in both respects. First, circular agents, having no ends, are exonuclease-resistant. Second, they bind complementary strands of RNA DNA with higher affinity than corresponding agents. We assessed the activity phosphodiester deoxynucleotides using chronic myeloid cell lines by targeting polypurine sequences. To represent cells bcr3/abl2-tγpe junction, we used K562 cells. A circle bcr sequence 385 nucleotides 5′ junction decreased number day 5 an IC50 9 µM. bcr2/abl2-tγpe BV173 bcr-abl itself 7 8 Control oligonucleotides, whether same uncircularized or circles nucleotide composition but scrambled sequence, had little effect. Unlike were stable when incubated 10% serum. The amount protein detected Western blotting specific anti-bcr-abl antibody at 24 hr antisense-treated was only that treated control circles, which demonstrates mechanism action. oligodeoxyribonucleotides (1) inhibit accumulation CML cells, (2) decrease per cell, (3) have sequence-selective activity, (4) more active containing base-pairing region.