ANTISENSE PROPERTIES OF END-MODIFIED OLIGONUCLEOTIDES TARGETED TO HA-RAS ONCOGENE

Phosphodiester oligodeoxyribonucleotides linked to an intercalating ag ent or a dodecanol tail or both complementary to the 12th codon region of Ha-ras mRNA were compared with the unmodified oligonucleotides of the same size and sequence with respect to their ability to induce RNa seH cleavage and antisense activity in cell culture. The hydrophobic t ail not only protected the oligonucleotide from nucleases but also enh anced RNase H cleavage of the target. Oligonucleotides carrying both a n acridine and a dodecanol substituent inhibited the proliferation of HBL100ras1 cells (human mammary cells stably transformed with the T24 Ha-ras gene carrying a G-->T point mutation in codon 12) at a 20-fold to 30-fold lower concentration than unmodified ones. Therefore, these modified oligonucleotides may prove useful for antisense applications.