Disclosed are synthetic, modified oligonucleotides complementary to, and capable of down-regulating the expression of, nucleic acid encoding protein kinase A subunit RI.sub..alpha.. The modified oligonucleotides have from about 15 to about 30 nucleotides and are hybrid, inverted hybrid, or inverted chimeric oligonucleotides. Also disclosed are therapeutic compositions containing such oligonucleotides and methods of using the same. In addition, therapeutic compositions and methods of their use are described which are directed to a synergistic effect resulting from the combination of oligonucleotides of the invention and other therapeutic compositions and methods.