Treatment of Malignant Gliomas with Antisense Oligonucleotides

摘要: Antisense oligonucleotides (ODNs) are single-stranded, chemically-modified DNA-like molecules for the inhibition of gene translation by sequence-specific knockdown mRNA through Watson–Crick hybridization. In general, their size ranges from 12 to 25 nucleotides in length, with majority ODNs being around 18–21 nucleotides. The natural phosphodiester backbone rapidly degraded biological fluids ubiquitous nucleases. Therefore, a variety heterocyclic modifications have been developed strengthen base-pairing and thus stabilize duplex formation between antisense ODN target mRNA. widely used determining function, validation drug targets and, finally, as novel therapeutics human diseases. this chapter, we will describe development including modifications, pharmacokinetics, toxicity animal models humans, preclinical clinical therapy high-grade gliomas. most advanced gliomas is phosphorothioate modified (S-ODN), AP 12009 (trabedersen), which encoding transforming growth factor beta2 (TGF-beta2). AP12009 administered intratumorally using convection-enhanced delivery (CED). A randomized, controlled international Phase III study recurrent or refractory anaplastic astrocytoma (SAPPHIRE) planned start early 2009. Further targeting malignant glioma Affinitak, PKC-alpha-S-ODN, an against IGF type I receptor ex vivo use. our opinion, potential applications cancer patients even long-term perspective. They can be designed specifically mRNA, sufficiently stable show first antitumor efficacy trials excellent profile. Additionally, techniques, like CED, may further improve pharmacological profile making them superior other DNA strategies humans.