Oligodeoxynucleotides phosphorothioated

Zhang, R., Diasio, R.B., Lu, Z., Liu, T., Jiang, Z., Galbraith, W.M. and Agrawal, S. (1995a) Pharmacokinetics and tissue disposition in rats of an oligodeoxynucleotide phosphorothioate (GEM 91) developed as a therapeutic agent for human immunodeficiency virus type-1. Biochem. Pharm., 49, 929-939. 

Zhang, R., Iyer, P., Yu, D., Zhang, X., Lu, Z., Zhao, H. and Agrawal, S. (1996) Pharmacokinetics and tissue disposition of a chimeric oligodeoxynucleotide phosphorothioate in rats following intravenous administration. J. Pharm. Exp. Ther., 278, 971-979. 

Agrawal, S., Temsamani, J. and Tang, J.Y. (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc. Natl. Acad. Sci. USA, 88, 7595-7579. 

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. 

Temsamani, J., Kubert, M., and Agrawal, S. (1993) A rapid method for quantitation of oligodeoxynucleotide phosphorothioates in biological fluids and tissues. Analytical Biochemistry, 215, 54 58. 

Zhang R, Yan J, et al. (1995). Pharmacokinetics of an anti-human immunodeficiency virus antisense oligodeoxynucleotide phosphorothioate (GEM 91) in HIV-infected subjects. Clin. Pharmacol. Ther. 58 44-53. 

Saijo Y, Perlaky L, Wang H, et al. (1994). Pharmacokinetics, tissue distribution, and stability of antisense oligodeoxynucleotide phosphorothioate ISIS 3466 in mice. Oncol. Res. 6 243-249. 

Stein, C. A. and Cohen, J. S., Phosphorothioate oligodeoxynucleotide analogues, in Oligodeoxynucleotides — Antisense Inhibitors of Gene Expression, Cohen, J. S., Ed., CRC Press, Boca Raton, FL, 1989, 97. 

Figure 5.12. Chemical structure of antisense oligodeoxynucleotides (AS-ODN). Phosphorothioate and methylphosphonate AS-ODN have a sulfur atom and a methyl group respectively, substituted for a nonbridging oxygen atom to increase stability to nucleases.

Previous studies have reported that ERKs are characteristically associated with cell proliferation and protection from apoptosis (Bl, XI), while activation of JNK and p38 MAPK can promote apoptosis in many systems, including B lymphocytes (G5), cerebellar granule cells (K3), hematopoietic cells (K8), and neuronal cells (M3, XI). On the other hand, a recent report found that a pyridinyl imidazole, SB 202190, the specific inhibitor of p38 MAPK, by itself was sufficient to induce apoptosis in T lymphocyte Jurkat cells (N2). Moreover, Th-2-derived cytokine IL-5, the ERK activator and antiapoptotic factor for eosinophils, could also activate p38 MAPK in human eosinophils (BIO). We recently reported that cytokine IL-3, IL-5, and GM-CSF could prolong survival of human eosinophilic leukemic (EoL-1) cells through the transient activation of ERK (W15). On the other hand, activation of p38 MAPK in EoL-1 cells by the NSAID sodium salicylate (NaSal) could lead to apoptosis (W15). We also found that the suppression of ERK using ERK antisense phosphorothioate oligodeoxynucleotides could promote the apoptosis of peripheral blood eosinophils (W16). Moreover, we found that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases (Z2). 

Phillips, J.A., Craig, S.J., Bayley, D., Christian, R.A., Geary, R. and Nicklin, P.L. (1997) Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem. Pharmacol, 54, 657-668. 

Wu, D., R. Boado, and W. Pardridge. 1996. Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. J Pharmacol Exp Ther 276 206. 

Table 4.1 Antisense phosphorothioate oligodeoxynucleotides studied in human clinical trials.

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. 

E. Chueng, and A.A. Levin. 2002. Development of an ultrasensitive noncompetitive hybridization-ligation enzyme-linked immunosorbent assay for the determination of phosphorothioate oligodeoxynucleotide in plasma. Anal. Biochem. 304 19-25. 

In animal studies, there is overwhelming evidence of biological activity of ASOs upon IV injection of simple solutions. Given the excellent solution stability and solubility possessed by phosphorothioate oligodeoxynucleotides, it has been rela-... 

Relative to the unmodified phosphorothioate oligodeoxynucleotides, these data demonstrate the increasing benefit of MOE substituents present as either a hemi-mer, with MOEs at the 3 -termini only or a gap-mer, with MOEs present at both the 3 - and 5 -termini and lastly, a full MOE substitution at every sugar location. These MOE gap-mer chemistries are demonstrating clinical efficacy by the subcutaneous... 

Stein CA, Tokinson JL, Yakubov L, Phosphorothioate oligodeoxynucleotides antisense inhibitors of gene expression Pharmacol Ther 1991 52 365-384,... 

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

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