Conceptual simplicity, the possibility of rational design, rel-atively inexpensive cost, and developments in the sequenc-ing of human genome have led to the use of short fragments of nucleic acid, commonly called oligonucleotides, either as therapeutic agents or as tools to study gene function. Fur-thermore, in the past decade, the development of antisense oligonucleotide technologies as therapeutics agents has led to Food and Drug Administration approval for the commer-cialization of the first antisense oligonucleotide, Vitravene (for cytomegalovirus retinitis; Refs. 1 and 2), and to numerous clinical trials of therapeutic oligonucleotides (3). The concept underlying antisense technology is relatively straightforward: the use of a sequence, complementary by virtue of Watson-Crick bp hybridization, to a specific mRNA can inhibit its expression and then induce a blockade in the transfer of genetic information from DNA to protein. How-ever, although antisense oligonucleotides are commonly in use now both in the laboratory and clinic, this theoretical simplicity belies the many questions concerning the molec-ular mechanisms of action of these compounds. It is our contention that a highly critical approach must still be taken in interpreting data derived from experiments using anti-sense oligonucleotides. It remains relatively easy to claim that experimentally observed biological effects occur by an antisense mechanism; nevertheless, it is also easy to ignore those nonspecific effects that can provide a virtually identical explanation of the observed phenotype, especially when ol-igonucleotides with phosphorothioate backbones are used. These themes will be expounded in some detail in this review.
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