Antisense oligonucleotide-based therapeutics for cancer

Abstract

There has been steady progress in antisense technology over the past 14 years. We now have a far better appreciation of the attributes and limitations of the technology. Antisense oligonucleotides have been used to selectively inhibit thousands of genes in mammalian cells, hundreds, if not thousands, of genes in rodents and other species and multiple genes in humans. There are over 20 antisense drugs currently in clinical trials, several of which are showing promising results. Like any other class of drugs in development, there will continue to be successes and failures in the clinic. Despite some disappointments with the technology, it appears to be a valid platform for both drug discovery and as an experimental tool for functionalizing genes. Advances in the medicinal chemistry and formulation of antisense oligonucleotides will further enhance their therapeutic and commercial potential.

Expression of VEGF-A/C, VEGF-R2, PDGF-α/Β, c-kit, EGFR, Her-2/Neu, Mcl-1 and Bmi-1 in Merkel cell carcinoma

“…40 Recently, several antisense oligonucleotides targeting genes involved in neoplastic progression have been evaluated as potential therapeutic agents, one of them being Mcl-1. [41][42][43] Mcl-1, a member of the Bcl-2 protein family, is an antiapoptotic protein [44][45][46] and functions by avoiding cell damage-induced mitochondrial cytochrome c release.…”

Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

“…The use of RNA interference (RNAi)-based strategies has recently become the technique of choice to silence gene expression in mammalian cell culture [1]. In typical strategies, 21-base pairs double stranded RNA (dsRNA) molecules, termed short interfering RNAs (siRNAs), with perfect complementarity to the target RNA are used as experimental triggers of mRNA breakdown.…”

Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma

“…Antisense oligonucleotides are designed to bind to RNA through Watson-Crick hybridization (4). The best characterized antisense mechanism of action involves cleavage of the target gene transcript by endogenous cellular nucleases, such as RNase H (5). Several chemical modifications have been developed to enhance the properties and effectiveness of antisense oligonucleotides.…”