Antisense compounds

Antiselective poisoning, 5 258 Antisense agents, 77 626-627 Antisense compounds, 77 13-14 Antisense mechanism, 77 627 Antisense oligonucleotides, 77 627, 628 Antiseptics, 3 605, 606... 

Novel approaches to therapeutically downregulate DNA methylation include the DNMTl antisense compound MG98. However, clinical phase trials with the single drug showed no effect (partial or complete remission) or the effects could not be linked to DNMT inhibition [95-97]. 

Moreover, the morpholino backbone s immunity to enzymatic attack avoids the potential for nonspecific interactions associated with degradation by-products. In contrast, modified nucleosides or nucleotides resulting from degradation of other antisense compounds might be toxic or might be incorporated into cellular genetic material and thereby lead to mutations or other undesired biologic effects. 

Cummings, J., Ward, T.H., LaCasse, E., Lefebvre, C., St Jean, M., Durkin, J., Ranson, M., and Dive, C. (2005) Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X linked inhibitor of apoptosis protein XIAP. British Journal of Cancer, 92, 532 538. 

The antisense sequence contains the complementary bases in an antiparallel arrangement. Thus, the definition of antisense compounds refers to their interaction with transcribed RNA. In a broader sense the term antisense action is also used to describe inhibition of mRNA processing by molecules binding to sites formed by tertiary structures of single-stranded mRNA and interaction of molecules with duplex DNA by sequence specific insertion into the grooves. 

The use of methylphosphonates (12) as antisense compounds has been reviewed by several authors [83,84]. Very good nuclease resistance and a different mechanism of membrane penetration are the most remarkable features of this ODN modification [85]. The lack of anionic charge however renders the compounds relatively insoluble in water. Drug/target duplexes do not activate RNase-H. Therefore, high concentrations of up to 100 pM are required to achieve antisense activity. Nevertheless, methylphosphonates seem to be suited elements of chimeric oligonucleotides. 

Phosphorothioate oligomers, 2 Hybridon has licensed certain antisense compounds to OriGenix Technologies in Jan. 1999. The underline bases in the phosphororthioate oligomers GEM 92,... 

Within this chapter, the authors have striven to obtain and validate the information in this field, concentrating on the chemistry of antisense compounds and giving more or less emphasis to different aspects according to their own experience, expectations and opinions. It is their hope that they may stimulate the readers interested in one or the other of the most fascinating lines of research in this new field of drug therapy. 

Most similar to RNAi compounds in their application and chemical nature are antisense compounds one of which, Vitravene, reached the market as an FDA-approved drug in 1998 [194,195]. Antisense oligonucleotides have been studied for their ability to knock down gene expression since 1978 [196, 197]. Later studies support that the mechanism of antisense inhibition acts either through the inhibition of translation or through RNase H-dependent degradation of mRNA [198]. 

Resten-GP, an antisense compound that interferes with the mRNA of a gene involved in the stenosis of vein grafts in coronary artery bypass grafting, is currently undergoing clinical trials. 

OGX-011, an antisense compound that inhibits clusterin, a cancer cell survival molecule, is currently in phase II trials for metastatic breast and prostate cancers. 

Kawasaki, AM. et al. Uniformly modified 2 -deoxy-2Afluoro phosphorothioate ohgonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets, /. Med. Chem., 36,831,1993. 

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