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Non-sequence-specific inhibition of transferrin receptor expression in HL-60 leukemia cells by phosphorothioate oligodeoxynucleotides.

A series of phosphodiester and phosphorothioate antisense oligodeoxynucleotides were synthesized against the human transferrin receptor (TfR). The phosphorothioate analogs exhibited marked biologic efficacy in culture, as assessed by inhibition of surface TfR content and HL-60 cell growth, whereas their unmodified phosphodiester counterparts were ineffective. Phosphorothioate oligodeoxynucleotides were more resistant to hydrolysis by serum and cellular nucleases and were more readily taken up by cells than phosphodiesters, thus providing a partial explanation for the differences in biologic activity. A length effect was observed, with antisense 30-mers exhibiting greater TfR inhibitory activity than 17-mers. The degree of receptor inhibition observed, however, was not sequence dependent, suggesting that the phosphorothioate oligodeoxynucleotides may have pleiotropic activities in eukaryotic cells in addition to inhibiting gene expression by classic antisense complementary binding to mRNA.