PAAn-1b and PAAn-E: Two phosphorothioate antisense oligodeoxynucleotides inhibit human aromatase gene expression

Estrogen-dependent diseases, especially breast cancers, are frequently trea ted with aromatase inhibitors. Another more recent strategy is the antisens e technology. In this study, after predicting aromatase mRNA secondary stru cture, we describe the design, the efficiency, and the toxicity of two anti sense phosphorothioate oligodeoxynucleotides (PAAn-1b and PAAn-E) directed toward aromatase mRNA, Indeed, 2 mu M PAAn-1b and PAAn-E encapsulated with 54 mu M polyethylenimine inhibit aromatase activity by 71 and 79%, respecti vely, in transfected 293 cells, with IC50 values of 0.2 and 0.6 mu M. The m echanism of inhibition ap pears to be specific after using sense and scramb le oligodeoxynucleotides as controls and largely decreases aromatase mRNA a nd protein amounts, Moreover, PAAn-1b and PAAn-E are not cytotoxic for 293 cells. This study finally provides a new strategy for aromatase inhibition, It offers new tools for studying aromatase gene expression and its role in cancer for instance, and this could be of help for the therapy of estrogen -dependent diseases. (C) 1998 Academic Press.