Download Antisense Therapeutics by Sudhir Agrawal PDF

By Sudhir Agrawal

Major researchers supply an authoritative survey and research of the newest findings at the swift improvement of antisense oligonucleotides healing and their software in numerous in vivo version structures. The book's high-profile members offer well timed debts in their state of the art thoughts, discussing such issues because the synthesis and purification of oligonucleotides, their choice for a selected gene aim, diverse tools of management, and using numerous telephone traces and mobile tradition structures. additionally they study questions of mobile uptake, in vitro organic task, in vivo organic job, the pharmacology and pharmacokinetics of oligonucleotides, and the applying of oligonucleotides to the crucial fearful procedure.

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Tonkinson, J L , and Yakubov, L. (1991) Phosphorothtoate ohgodeoxynucleottdes-anttsense inhibitors of gene expression? , Matteucci, M. , and Martm, J. C. (1993) Current concepts in antisense drug design J Med Chem 36, 1923-1937. Stem, C A. -C (1993) Antisense oligonucleottdes as therapeuttc agents-Is the bulllet really magical? , and Neckers, L. M. 343-350. 42 Bennett et al. 14 KitaJima, I , Shmohara, T , Btlakovics, J , Brown, D A , Xu, X , and Nerenberg, M (1992) Ablation of transplanted HTLV-1 tax-transformed tumors m mace by antisense mhibitton of NF-kB Sczence 258, 1792-I 795 15.

If this were the case, phosphorothioate ODN should be cleared with kinetics similar to inulm following a bolus injection. When phosphorothioate ODN with internal fluorescein label was mjected as an mtraventricular bolus, the level of fluorescence in CSF closely matched the (3H) level over a 100-min time-course. Thus, ~5% of the material sampled 5 min after injection could be detected by 100 mm. In contrast to the fmdmgs with phosphodiester material, gel electrophoretic analysis of CSF samples following phosphorothioate bolus injection revealed only intact ODN even after 50 Neckers et al.

Unpublished observations). When equal amountsof fluorescent brain extract from phosphodiester and phosphorothioate mfusates were examined by gel electrophorests, little intact phosphodiester material was found, whereas the phosphorothioate ODN extracted was only partially degraded. McCarthy et al. (Z9) also reported that phosphorothioate ODN, injected into brain parenchyma, remained largely intact 52 Neckers et al. for at least 5 h. Contmuous mfttsron of phosphorothroate ODN drrectly mto brain tissue has the potential to deliver focally high concentrations of ODN, with a strong concentratton gradient to the rest of the brain We have recently begun to examine admmrstratron of ODN to growing ghoblastoma tumors by contmuous infusion.

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