ANTISENSE PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES - INTRODUCTORY CONCEPTS AND POSSIBLE MOLECULAR MECHANISMS OF TOXICITY

Over the past 5 years or so, much attention has been given to the poss ible use of synthetic antisense oligonucleotide analogs as a new class of therapeutic agents that function by sequence-specific inhibition o f genetic expression. The basic design concepts which underline this n ovel approach to drug discovery are briefly described herein, together with some of the chemical, biochemical, and pharmacological aspects o f phosphorothioate oligodeoxynucleotides that are first-generation ant isense compounds now under clinical investigation. Possible molecular mechanisms of toxicity for this class, and other structural types of a ntisense compounds are discussed with the hope of stimulating interest in future toxicological studies in this emerging area of drug develop ment.