Second generation of antisense agents with segments of modified phosphorothioate oligonucleotides. The most extensively studied and used agents contain 2'-substituted modifications, such as 2'-O-methyl. In animal models, such modifications were associated with improved in vivo stability, oral bioavailability, and markedly decreased concentration-related adverse events that were common for the first generation of oligonucleotides and have been attributed to sequence-independent and sequence-specific effects. (NCI)