Antisense drugs phosphorothioates

Geary RS, Yu RZ, Siwkowski A. Pharmacokinetic/pharmacodynamic properties of phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotides in animals and man. In Crooke ST, ed. Antisense Drug Technology. New York Dekker, 2007. 

Human Safety. At Isis, we have had the opportunity to study approximately 10 phosphorothioate oligonucleotides in humans. We have studied antisense drugs administered intravitreally, intradermally, subcutaneously, intravenously, and topically. Vitravene, an intravitreally administered drug, is commercially available around the world. 

Figure 3.8 Mode of action for antisense drugs. An example is Fomivirsen (Vitravene, Isis Pharmaceuticals), which is a 21-nucleotide phosphorothioate that binds to the complementary mRNA of cytomegalovirus and blocks the translation process. Cytomegalovirus is a virus that belongs to the herpes group, source Chang, Y.T., Keyword of the Post Genomic Era—Library, New York University, 2002, http //www.nvu.edu/classes/vtchanq/book/e003.html [accessed Sep 10,2002],...

Some oligonucleotide modifications, however, do support RNase H activity. One of the first generation of antisense drugs developed, phosphorothioates (shown in Figure 1), falls in this category 14). While this... 

Stein D, Foster E, Huang SB, Weller D, Summerton J (1997) A spedfidty comparison of four antisense types morphoUno, 2 -0-methyl RNA, DNA, and phosphorothioate DNA, Antisense Nucleic Acid Drug Dev 7 151-157... 

Peng, B., Andrews, J., Nestorov, I., Brennan, B., Nicklin, P. and Rowland, M. (2001) Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Develop., 11, 15-27. 

D.K. Monteith, and A.A. Levin. 1997. Antisense oligonucleotide inhibitors for the treatment of cancer 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anti-Cancer Drug Design 12 383-393. 

A. Roskey, and S. Agrawal. 1998. Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91) in cynomolgus monkeys following intravenous infusion. Antisense Nucleic Acid Drug Dev. 8 43—52. 

J. Matson, H. Sasmor, L. Cummins, and A.A. Levin. 2003. Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2 -0-(2-methoxyethyl) modified antisense oligonucleotide comparison across species. Drug Metah. Dispos. 31 1419-1428. 

Yu, R.Z., J.Q. Su, J.S. Grundy, R.S. Geary, K.L. Sewell, A. Dorr, and A.A. Levin. 2003. Prediction of clinical responses in a simulated phase III trial of Crohn s patients administered the antisense phosphorothio-ate oligonucleotide ISIS 2302 comparison of proposed dosing regimens. Antisense Nucleic Acid Drug Dev. 13 57-66. 

Summerton J, Stein D, Huang B, Matthews R Weller D, Partridge M, Morpholino and phosphorothioate antisense oligomers compared in cell-free and in-cell systems, Antisense Nucleic Acid Drug Dev 1997 7 63-70,... 

Geary RS, Yu RZ, Levin AA. Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr Opin Invest Drugs 2001 2(4) 562-73. 

Henry SP, Novotny W, Leeds J, Auletta C, Kornbrust DJ. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucl Acid Drug Dev 1997 7 503-10. 

Zhao Q,Temsamani J, Zhou R-Z, Agrawal S. Pattern and kinetics of cytokine production following administration of phosphorothioate oligonucleotides in mice. Antisense NuclAcid Drug Dev 1997 7 495-502. 

Among DNA-based drugs, only antisense DNA is currently analyzed by capillary electrophoresis. Antisense DNA therapy requires reliable and convenient methods for sequencing short single-stranded oligonucleotides. A method for phosphorothioate antisense DNA sequencing by capillary electrophoresis coupled to UV detection has been developed based on a modified chain-termination sequencing method.Capillary gel electrophoresis alone or in combination with HPLC is also used for pharmacokinetics study of antisense... 

In conclusion, phosphorothioate oligonucleotides may interact with a wide range of proteins through several types of mechanisms. These interactions may influence the pharmacokinetic, pharmacologic, and toxicologic properties of these molecules. They may also complicate studies on the mechanism of action of these drugs, and may obscure an antisense activity. For example, phosphorothio-... 

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