Antisense Alternatives

An alternative strategy in this era of molecular therapeutics is the antisense approach in which antisense oligonucleotides (AS-ODNs) hybridize to complementary sequences of target RNA, resulting in the prevention of message translation into protein product. This is generally achieved by activation of the enzyme RNase H that recognizes the RNA:DNA duplex and cleaves the target RNA or by steric blocking at the ribosome (reviewed by Crooke [11]). Thus, in theory, antisense technology has the potential to selectively correct aberrant gene expression that may be related to many diseases (12). Chemical modifications of AS-ODNs are required to limit degradation by serum exonucleases and intracellular exo- and endonucleases. Phosphorothioates, possessing sulfur substitutions at nonbridging oxygens on the phosphate backbone, were the first generation of AS- ODNs to enter clinical studies. Vitravene® (fomivirsen; Isis/Ciba Vision) was the first phosphorathioate oligonucleotide (P-ODN) to be licensed in 1998. Vitravene is a 21mer P-ODN that targets the major immediate-early gene of cytomegalovirus (CMV) and is administered by intravitreal injection to patients with acquired immunodeficiency syndrome for the treatment of CMV-induced retinitis (13). However, systemic administration of antisense phosphorothioates in preclinical models and clinical trials can result in toxic side effects that are unrelated to target inhibition. In this chapter, we review AS-ODNs that have entered clinical trials for cancer therapy. The mRNA targets of the AS-ODNs are given in Table 1 and stages of clinical development in Table 2.

Table 1

mRNA Targets for AS-ODNs in Clinical Trials



RNA-binding region






Exon 10


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