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Phosphorothioate Oligodeoxynucleotides as Inhibitors Of Gene Expression: Antisense and Non-Antisense Effects

  • Chapter
Applications of Antisense Therapies to Restenosis

Part of the book series: Perspectives in Antisense Science ((DARE,volume 3))

Abstract

Substantial progress has been made in the past several years in the development and use of oligonucleotide analogs as pharmacological tools and as therapeutic agents. Oligonucleotides are short single strand DNA molecules which target messenger RNA (mRNA). These compounds have many advantages over more traditional protein-targeted drugs. During the process of transcription, every gene gives a rise to a multiple copies of mRNA, these are then translated into a very large number of protein molecules. Thus, inhibition of gene expression should be more efficient at the level of mRNA than at the level of protein. If a disease is known to be caused by inappropriate production or abnormal function of a specific protein, antisense oligonucleotides can be rationally designed and tested simply on the basis of the sequence of the gene encoding that protein. A theoretically greater advantage is the specificity by which these molecules act on their target receptor. A drug is considered specific if it has a high binding affinity for its receptors relative to other binding sites. Traditional drugs typically have limitations (i.e., toxicity) because of their lack of specificity. Due to the specificity of the Watson-Crick base-pair interaction, oligonucleotide-based drugs have the theoretical potential to be orders of magnitude more specific than traditional drugs. This raises the possibility that antisense oligonucleotides can be used not only as research tools, but more importantly, developed as a completely new class of drugs.

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References

  1. Nielsen, P.E., Engholm, M., Berg, R.H. & Buchardt, O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science. 1991; 254: 1497–1500.

    PubMed  CAS  Google Scholar 

  2. Mollegaard, N.E., Buchardt, O., Engholm, M. & Nielsen, P.E. PNA-DNA strand displacement loops as artificial transcription promoters. Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 3892–3895.

    PubMed  CAS  Google Scholar 

  3. Sun, J.-S. & Helene, C. Oligonucleotide-directed triple-helix formation. Curr. Opin. Struct. Biol. 1993; 3: 345–356.

    CAS  Google Scholar 

  4. Bielinska, A., Shivdasani, R.A., Zhang, L. & Nabel, G.J. Regulation of gene expression with double-stranded phosphorothioate oligonucleotides. Science. 1990; 250: 997–1000.

    PubMed  CAS  Google Scholar 

  5. Stein, C.A. & Cheng, Y.-C. Antisense oligonucleotides as therapeutic agents — is the bullet really magical. Science. 1993; 261: 1004–1012.

    PubMed  CAS  Google Scholar 

  6. Wagner, R.W. Gene inhibition using antisense oligodeoxynucleotides. Nature. 1994; 372: 333–335.

    PubMed  CAS  Google Scholar 

  7. Zon, G. Oligonucleotide analogues as potential chemotherapeutic agents. Pharm. Res. 1988; 5: 539–549.

    PubMed  CAS  Google Scholar 

  8. Dolnick, B.J. Antisense agents in pharmacology. Biochem. Pharmacol. 1990; 40: 671–675.

    PubMed  CAS  Google Scholar 

  9. Helene, C.& Toulme, J.-J. Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim. Biophys. Acta 1990; 1049: 99–125.

    PubMed  CAS  Google Scholar 

  10. Neckers, L., Whitesell, L., Rosolen, A. & Geselowitz, D.A. Antisense inhibition of gene expression. Crit. Rev. Oncogenesis. 1992; 3: 175–231.

    PubMed  CAS  Google Scholar 

  11. Tonkinson, J.L. & Stein, C.A Antisense oligodeoxynucleotides as clinical therapeutic agents. Cancer Investig. 1996; 14: 54–65.

    CAS  Google Scholar 

  12. Crooke, S.T. Progress in antisense therapeutics. Med. Res. Rev. 1996; 16: 319–344.

    PubMed  CAS  Google Scholar 

  13. Thein, S.L. & Wallace, R.B. The use of synthetic oligonucleotides as specific hybridization probes in the diagnosis of genetic disorders. In: Human Genetic Diseases: A Practical Approach. Davies, K.E., ed., IRL Press, Oxford, 1986; p.33.

    Google Scholar 

  14. Paterson, B.M., Roberts, B.E. & Kuff, E.L. Structural gene identification and mapping by DNA-mRNA hybrid-arrested cell-free translation. Proc. Natl. Acad. Sci. U.S.A. 1977; 74: 4370–4374.

    PubMed  CAS  Google Scholar 

  15. Kawasaki, E.S., Quantitative hybridization-arrest of mRNA in Xenopus oocytes using single-stranded complementary DNA or oligonucleotide probes. Nucleic Acids Res. 1985; 13: 4991–5004.

    PubMed  CAS  Google Scholar 

  16. Haeuptle, M.T., Frank, R. & Dobberstein, B. Translational arrest by oligodeoxynucleotides complementary to mRNA coding sequences yields polypeptides of predetermined length. Nucleic Acids Res.1986; 14: 1427–1445.

    PubMed  CAS  Google Scholar 

  17. Minshull, J. & Hunt, T. The use of single-stranded DNA and RNase H to promote quantitative “hybrid arrest of translation” of mRNA-DNA hybrids in reticulocite lysate cell-free translations. Nucleic Acids Res. 1986; 14: 6433–6451.

    PubMed  CAS  Google Scholar 

  18. Hausen, P. & Stein, H. Ribonuclease H. An enzyme degrading the RNA moiety of DNA-RNA hybrids. Eur. J. Biochem. 1970; 14: 278–283.

    PubMed  CAS  Google Scholar 

  19. Walder, R.Y. & Walder, J.A. Role of RNase H in hybrid-arrested translation by antisense ligonucleotides. Proc. Natl. Acad. Sci. U.S.A. 1988; 85: 5011–5015.

    PubMed  CAS  Google Scholar 

  20. Tidd, D.M. A potential role for antisense oligonucleotide analogues in the development of oncogene targeted cancer chemotherapy. Anticancer Res. 1990; 10: 1169–1182.

    PubMed  CAS  Google Scholar 

  21. Breslauer, K.J., Frank, R., Blocker, H. & Marky, L.A. Predicting DNA duplex stability from base sequence. Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 3746–3750.

    PubMed  CAS  Google Scholar 

  22. Freier, S.M., Kierezek, R., Jaeger, J., Sugimoto, N., Caruthers, M.H., et al. Improved free-energy parameters for predictions of RNA duplex stability. Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 9373–9377.

    PubMed  CAS  Google Scholar 

  23. Freier, S.M., Lima, W.F., Sanghvi, Y.S., Vickers, T., Zounes, M, et. al. Thermodynamics of antisense oligonucleotide hybridization. In Gene Regulation by Antisense Nucleic Acids. Izant, J. and Erickson, R., Eds., Raven Press, New York, 1992 p.95–107.

    Google Scholar 

  24. Uhlmann E. & Peyman, A. Antisense oligonucleotides: a new therapeutic principle. Chem. Rev. 1990; 90: 544–584.

    Google Scholar 

  25. Monia, B.P., Johnston, J.F., Ecker, D.J., Zounes, M.A., Lima, W.F. & Freier, S. Selective inhibition of mutant Ha-ras mRN A expression by antisense oligonucleotides. J. Biol. Chem. 1992; 267: 1995–19962.

    Google Scholar 

  26. Woolf, T.M., Melton, D.A. & Jennings, C.G.B. Specificity of antisense oligonucleotides in vivo. Proc. Natl. Acad. Sci. U.S.A. 1992; 91: 1356–7309.

    Google Scholar 

  27. Cohen, J. Introduction: strategies and realities. In: Antisense inhibition of gene expression. Cohen, J. (ed.), CRC Press: Boca Raton, F1. 1989; p.1.

    Google Scholar 

  28. Caruthers, M., Barone, A.D., Beaucage, S.L., Dodds, R., Fisher, E.F. et al. Chemical synthesis of deoxynucleotides by the phosphoramidite method. Methods Enzymol. 1987; 154; 287–313.

    PubMed  CAS  Google Scholar 

  29. Zon, G. & Geizer T. Phosphorothioate oligonucleotides: Chemistry, purification, analysis, scale-up and future directions. Anti-Cancer Drug Des. 1991; 6: 539–541.

    CAS  Google Scholar 

  30. Wickstrom, E. Oligodeoxynucleotide stability in subcellular extracts and culture media. J. Biochem. Biophys. Methods 1986; 13: 97–102.

    PubMed  CAS  Google Scholar 

  31. Eder, P.S., Devine, R.J., Dagle, T.M., Walder, J.A. Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3′ exonuclease in plasma. Antisense Res. Dev. 1991; 1: 141–151.

    PubMed  CAS  Google Scholar 

  32. Goodchild, J. Conjugates of oligonucleotides and modified oligonucleotides: a review of their synthesis and properties. Bioconjugate Chemistry. 1990; 1: 167–191.

    Google Scholar 

  33. Morvan, F., Rayner, B. & Imbach, J.-L. α-Oligonucleotides: a unique class of modified chimeric nucleic acids. Anti-Cancer Drug Design. 1991; 6: 521–529.

    PubMed  CAS  Google Scholar 

  34. Stein, C.A., Tonkinson, J. & Yakubov, L. Phosphorothioate oligodeoxynucleotides-antisense inhibitors of gene expression?Pharmacol.Ther. 1991; 52: 365–384.

    PubMed  CAS  Google Scholar 

  35. Stein, C.A., Mori, K.A., Loke, S.L., Subashinge, C., Shinozuka, K., et al. Phosphorothioate and normal oligodeoxynucleotides with 5′-linked acridine: characterization and preliminary kinetics of cellular uptake.Gene 1988; 72: 333–341.

    PubMed  CAS  Google Scholar 

  36. Dean, N.M., McKay, R., Miraglia, L., Geiger, T., Muller, M., Fabbro, D.& Bennett, C.F. Antisense oligonucleotides as inhibitors of signal transduction: development from research tools to therapeutic agents. Biochem. Soc. Trans. 1996; 24: 623–629.

    PubMed  CAS  Google Scholar 

  37. Bacon, T.A. & Wikstrom E. Walking along human c-myc mRNA with antisense oligodeoxynucleotides: maximum efficacy at the 5′cap region. Oncogene Res. 1991; 6: 13–19.

    PubMed  CAS  Google Scholar 

  38. Goodchild, J. In Oligodeoxynucleotides, antisense inhibitors of gene expression. J. Cohen, Ed. (Macmillan, London, 1989), pp.53–57.

    Google Scholar 

  39. Stull, R.A., Taylor, L.A., Szoka, F.C., Jr. Predicting antisense oligonucleotide inhibitory efficacy: a computational approach using histograms and thermodynamic indices. Nucleic Acids Res. 1992; 20: 3501–3508.

    PubMed  CAS  Google Scholar 

  40. Wang, S., Dolnick, B.J. Quantitaive evaluation of intracellular sense: antisense RNA hybrid duplexes. Nucleic Acids Res. 1993; 21: 4383–4391.

    PubMed  CAS  Google Scholar 

  41. Kozak, M. Influences of mRNA secondary strusture on initiation by eucariotic ribosomes. Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 770–777.

    Google Scholar 

  42. Speir, E., Epstein, S.E. Inhibition of smooth muscle cell proliferation by an antisense oligodeoxynucleotide targeting the mRNA encoding PCNA. Circulation. 1992; 86: 538–547.

    PubMed  CAS  Google Scholar 

  43. Chiang, M.Y., Chan, H., Zounes, M.A, Freier, S.M., Lima, W.F., Bennett, C.F. Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J. Biol. Chem. 1991; 266: 18162–18171.

    PubMed  CAS  Google Scholar 

  44. Dean, N.M. and McKay, R. Inhibition of protein-kinase C-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 11762–11766.

    PubMed  CAS  Google Scholar 

  45. Dean, N.M., McKay, R., Condon, T.P. and Bennett, C.F.Inhibition of protein kinase C-α expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J. Biol. Chem. 1994; 269: 16416–16424.

    PubMed  CAS  Google Scholar 

  46. Monia, B.P., Johnston, J.F., Geiger, T., Muller, M.& Fabro, D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nature Med. 1996; 2: 668–675.

    PubMed  CAS  Google Scholar 

  47. Stec, W.J., Zon, G., Egan, W., and Stec, B. Automated solid-phase synthesis, separation, and stereochemistry of phosphorothioate analogues of oligodeoxyribonucleotides. J. Am. Chem. Soc. 1984; 106: 6077–6079.

    CAS  Google Scholar 

  48. Caruthers, M.H. Gene syntheses machines: DNA chemistry and its uses. Science (Wash. DC), 1985; 230: 281–285.

    CAS  Google Scholar 

  49. La Planche, L.A., James, T. L., Powell, C., et al. Phosphorothioate-modified oligodeoxyribonucleotides III. NMR and UV spectroscopic studies of Rp-Rp, Sp-Sp and Rp-Sp duplexes derived from stereoisomeric O-ethyl phosphorothioates. Nucleic Acids Res. 1986; 14: 9081–9093.

    Google Scholar 

  50. Stein, CA., Subashinghe, C., Shinozuka, K. and Cohen, J.S.Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res. 1988; 16: 3209–3221.

    PubMed  CAS  Google Scholar 

  51. Cowsert, L.M., Fox, M.C., Zon, G., Mirabelli, C.K. In vitro evaluation of phosphorothioate oligonucleotides targeted to the E2 mRNA of papillomavirus: potential tretment for genital warts. Antimicrob. Agents Chemother. 1993; 37: 171–177.

    PubMed  CAS  Google Scholar 

  52. Eckstein, F. Investigation of enzyme mechanisms with nucleoside phosphorothioates. Annu. Rev. Biochem. 1985; 54: 357–402.

    Google Scholar 

  53. Crooke, R.M., Graham, M.J., Cooke, M.E.and Crooke, S.T. In vitro pharmacokinetics of phosphorothioate antisense oligonucleotides. J. Pharmacol. Exp. Ther. 1995; 275: 462–473.

    PubMed  CAS  Google Scholar 

  54. Agrawal., S., Temsamani, J., Tang, J.Y. Pharmacokinetics, biodistribution and stability of oligodeoxynucleotide phosphorothioates in mice. Proc. Natl. Acad. Sci. U.S.A. 1991; 88: 7595–7599.

    PubMed  CAS  Google Scholar 

  55. Gao, W., Han, F., Stotrm, C., Egan, W. & Cheng, Y.C. Phosphorothioate oligonucleotides are inhibitors of human DNA polymerases and RNase H: Implications for antisense technology. Molec. Pharmacol. 1992; 41: 223–229.

    CAS  Google Scholar 

  56. Zon, G. & Stec, W.J. Phosphorothioate oligonucleotides. In: Oligonucleotides and their analogues: A Practical Approach, pp. 87–108, Eckstein, F. (ed.) IRL Press: Oxford. 1991

    Google Scholar 

  57. Benimetskaya, L., Tonkinson, J.L., Koziolkiewicz, M., Karwowski, B., Guga, P., Zeltser, R., Stec, W. & Stein, C.A. Binding of phosphorothioate oligodeoxynucleotides to basic fibroblast growth factor, recombinant soluble CD4, laminin and fibronectin is P-chirality independent. Nucleic Acids Res. 1995; 23: 4239–4245.

    PubMed  CAS  Google Scholar 

  58. Loke, S.L., Stein, C.A., Zhang, X.H., Mori, K., Nakanishi, M.,et al. Characterization of oligonucleotide transport into living cells. Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 3474–3478.

    PubMed  CAS  Google Scholar 

  59. Yakubov, L.A., Deeva, E.A., Zarytova, V.F., Ivanova, E.M., Ryte, A.S., Yurchenko, L.V. & Vlassov, V.V. Mechanism of oligonucleotide uptake by cells: Involvement of specific receptors? Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 6454–6458.

    PubMed  CAS  Google Scholar 

  60. Stein, C., Tonkinson, J., Zhang, L., et al. Dynamics of the internalization of phosphodiester oligonucleotides in HL60 cells. Biochemistry 1993; 32: 4855–4861.

    PubMed  CAS  Google Scholar 

  61. Wu-Pong, S., Weiss, T., Hunt, C.A. Calcium-dependent cellular uptake of a c-myc antisense oligonucleotide. Cell. Molec. Biol. 1994; 40: 843–850.

    CAS  Google Scholar 

  62. Benimetskaya, L., Loike, J.D., Khaled, Z., Loike, G., Silverstein, S.C., Cao, L., Khoury, J.E., Cai, T-Q. and Stein, C.A. Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nature Med. 1997; 3: 414–420.

    PubMed  CAS  Google Scholar 

  63. Tonkinson, J.L., Stein, C.A. Patterns of intracellular compartmentalization, trafficking and acidification of 5′-fluorescein labeled phosphodiester and phosphorothioate oligodeoxynucleotides in HL60 cells. Nucleic Acids Res. 1994; 22: 4268–4275.

    PubMed  CAS  Google Scholar 

  64. Stein, C.A. Controversies in the cellular pharmacology of oligodeoxynucleotides. Antisense Nucleic Acid Drug Devel. 1997; 7: 207–209.

    CAS  Google Scholar 

  65. Bennett, C.F., Chiang, M.-Y., Chan, H., Shoemaker, J.E.E., Mirabelli, C.K.Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Molec. Pharmacol. 1992; 41: 1023–1033.

    CAS  Google Scholar 

  66. Agrawal., S., Temsamani, J., Galbraith, W. & Tang, J. Pharmacokinetics of antisense oligonucleotides. Clin. Pharmacokinet. 1995; 28: 7–16.

    PubMed  CAS  Google Scholar 

  67. Cossum, P.A., Truong, L., Owens, S.R., Markham, P.M., Shea, J.P., Crooke, S.T. Pharmacokinetics of a 14C-labeled phosphorothioate oligonucleotide, ISIS 2105, after intradermal administration to rats. J. Pharmacol. Exp. Ther. 1994; 269: 89–94.

    PubMed  CAS  Google Scholar 

  68. Casenave, C., Loreau, N., Toulme, J.J., Helene, C. Anti-messenger oligodeoxynucleotides: specific inhibition of rabbit beta-globin synthesis in wheat germ extracts and Xenopus oocytes. Biochimie. 1986; 68: 1063–1069.

    Google Scholar 

  69. Bennett, M.R., Schwartz, S.M. Antisense therapy for angioplasty restenosis. Some critical considerations. Circulation. 1995; 92: 1981–1993.

    PubMed  CAS  Google Scholar 

  70. Lenguel, P. Biochemistry of interferons and their actions. Annu. Rev. Biochem. 1982; 51: 251–282.

    Google Scholar 

  71. Memet, S., Besanco, F., Bourgeade, M.F., Thang, M.N. Direct induction of interferon-gamma and interferon-alpha/beta inducible genes by double-stranded RNA. J. Interferon Res. 1991; 11: 131–141.

    PubMed  CAS  Google Scholar 

  72. Yamamoto, S., Yamamoto, T., Kataoka, T., Kuramoto, E., Yano, O., Tokunaga, T. Unique palindromic sequences in synthetic oligonucleotides are required to induce INF and augment INF-mediated natural killer activity. J.Immunol. 1992; 148: 4072–4076.

    PubMed  CAS  Google Scholar 

  73. Kuramoto, E., Yano, O., Kimura, Y., Baba, M., Makino, T., Yamamoto, S., Yamamoto, T., Kataoka, T., Tokunaga, T. Oligonucleotide sequences required for natural killer cell activation. Jpn. J. Cancer Res. 1992; 83: 1128–1131.

    PubMed  CAS  Google Scholar 

  74. Krieg, A.M., Yi, A.-K., Matson, S., Waldschmidt, T.J., Bishop, G.A., Teasdale, R., Koretsky, G.A., Klinman, D.M.CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995; 374: 546–549.

    PubMed  CAS  Google Scholar 

  75. Mclntyre, K.W., Lombard-Gilloly, K., Perez, J.R., Kunsch, C., Sarmiento, U.M., Lagiran, J.D., Landreth, K.T., Narayanan, R. A sense phosphorothioate oligonucleotide directed to the initiation codon of transcription factor NF-κB p65 causes sequence-specific immune stimulation. Antisense Res. Dev. 1993; 3: 309–322.

    Google Scholar 

  76. Vaerman, J.L., Moureau, P., Deldime, F., Lammineur, C., Morschauser, F.,and Martiat, P. Antisense oligodeoxyribonucleotides suppress hematologic cell growth through stepwise release of deoxyribonucleotides. Blood 1997; 90: 331–339.

    PubMed  CAS  Google Scholar 

  77. Guga, P., Koziolkiewicz, M., Okruszek, A., and Stec, W. Oligo(nucleosidephosphorothioate)s; In Applied Antisense Oligonucleotide Technology. C Stein and A. Krieg (Eds), John Wiley, New York, 1998; p.23–50.

    Google Scholar 

  78. Potter, B.V.L., Eckstein, F. Cleavage of phosphorothioate substituted DNA by restriction endonucleases. J. Biol. Chem. 1984; 259: 14243–14248.

    PubMed  CAS  Google Scholar 

  79. Guvakova, M.A., Yakubov, L.A., Vlodavsky, I., Tonkinson, J.L.and Stein, C.A. Phosphorothioate oligonucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix. J. Biol. Chem. 1995; 270: 2620–2627.

    PubMed  CAS  Google Scholar 

  80. Stein, C.A., Krieg, A.M. Problems in interpretation of data derived form in vitro and in vivo use of antisense oligonucleotides. Antisense Res. Dev. 1994; 4: 67.

    PubMed  CAS  Google Scholar 

  81. Epstein, S.T., Speir, E., Unger, E.F.et al. The basis of molecular strategies for treating coronary restenosis after angioplasty. J. Amer. Coll. Cardiol. 1994; 23: 1278–1288.

    CAS  Google Scholar 

  82. Simons, M., Edelman, E.R., DeKeyser, J.L., Langer, R., Rosenberg, R.D. Antisense c-myb oligonucleotides inhibit intimai arterial smooth muscle cell accumulation in vivo. Nature 1992; 359: 67–70.

    PubMed  CAS  Google Scholar 

  83. Shi, Y., Hutchinson, H.G., Hall, D.J. et al. Downregulation of c-myc expression by antisense oligonucleotides inhibits proliferationof human smooth muscle cells. Circulation. 1993; 88: 1190–1195.

    PubMed  CAS  Google Scholar 

  84. Bennett, M.R., Anglin, S., McEwan, J.R. et al. Inhibition of vascular smooth muscle cell proliferation in vitro and in vivo by c-myc antisense oligonucleotides. J. Clin. Invest. 1994; 93: 820–828.

    PubMed  CAS  Google Scholar 

  85. Yakubov, L., Khaled, Z., Zhang, L.-M., Truneh, A., Vlassov, V. & Stein, C.A. Oligodeoxynucleotides interact with recombinant CD4 at multiple sites. J. Biol. Chem. 1993; 268: 18818–18823.

    PubMed  CAS  Google Scholar 

  86. Maury, G., Alaoui, A.E., Morvan, F., Muller, B., Imbach, J.-L., Goody, R.S.Template-phosphorothioate oligodeoxynucleotide duplexes as inhibitors of HIV-1 reverse transcriptase. Biochem. Biophys. Res. Commun. 1992; 186: 1249–1256.

    PubMed  CAS  Google Scholar 

  87. Stein, C.A., Cleary, A.M., Yakubov, L. & Lederman, S. Phosphorothioate oligodeoxynucleotides bind to the third variable loop domain (v3) of human immunodeficiency virus type 1 gp120. Antisense Res. Devel. 1993; 3: 19–31.

    CAS  Google Scholar 

  88. Gao, W.-Y., Han, F.-S., Storm, C., Egan W., Cheng, Y.-C. Phosphorothioate oligonucleotides are inhibitors of human DNA polymerases and RNase H: Implications for antisense technology. Mol. Pharmacol. 1992; 41: 223–229.

    PubMed  CAS  Google Scholar 

  89. Bennett, C.F., Chiang, M.Y., Wilson-Lingardo, L. and Wyatt, J.Sequence specific inhibition of human type II phospholipase A2 enzyme activity by phosphorothioate oligonucleotides. Nucleic Acids Res. 1994; 22: 3202–3209.

    PubMed  CAS  Google Scholar 

  90. Perez, J.R., Li, Y., Stein, C.A., Majumder, S., Oorshot, A.V., Narayanan, R. Sequence-independent induction of Spl transcription factor activity by phosphorothioate oligodeoxynucleotides. Proc. Natl. Acad. Sci. U.S.A 1994; 91: 5957–5961.

    PubMed  CAS  Google Scholar 

  91. Teasdale, R.M., Matson, S.J., Fisher, E., Krieg, A.M. Inhibition of T4 polynucleotide kinase activity by phosphorothioate and chimeric oligodeoxynucleotides. Antisense Res. Dev. 1994; 4: 295–297.

    PubMed  CAS  Google Scholar 

  92. Bergan, R., Connell, Y., Fahmy, B., Kyle, E., Neckers, L. Aptameric inhibition of p210bcr-abl tyrosine kinase autophosphorylation by oligodeoxynucleotides of defined sequence and backbone structure. Nucleic Acids Res. 1994; 22: 2150–2154.

    PubMed  CAS  Google Scholar 

  93. Watson, P.H., Ro, R.T., Shiu, R.P.C. Inhibition of cell adhesion to plastic substratum by phosphorothioate oligonucleotide. Exp.Cell. Res. 1992; 202: 391–397.

    PubMed  CAS  Google Scholar 

  94. Chavany, C., Connell, Y., Neckers, L. Contribution of sequence and phosphorothioate content to inhibition of cell growth and adhesion caused by c-myc antisense oligomers. Mol. Pharmacol. 1995; 48: 738–746.

    PubMed  CAS  Google Scholar 

  95. Khaled, Z., Benimetskaya, L., Seltser, R., Khan, T., Sharma, H.W., Narayanan, R. & Stein, C.A. Multiple mechanisms may contribute to the cellular anti-adhesive effects of phosphorothioate oligonucleotides. Nucleic Acids Res. 1996, 24: 737–745.

    PubMed  CAS  Google Scholar 

  96. Wang, W., Chen, H.J., Warshofsky, M., Schwartz, A, Stein, C.A., Rabbani, L.E. Effects of S-dC28 on vascular smooth muscle cell adhesion and plasminogen activator production. Antisense Nucleic Acid Drug Devel. 1997; 7: 101–107.

    CAS  Google Scholar 

  97. Vlassov, V.V., Pautova, L.V., Rykova, E.Iu.& Iakubov, L.A. Interactions of oligonucleotides with blood serum proteins. Biokhimia. 1993; 58: 1247–1251.

    Google Scholar 

  98. Neckers, L.M. and Iyer, K. Nonantisense effects of antisense oligonucleotides. In Applied Antisense Oligonucleotide Technology. C. Stein and A Krieg (Eds), John Wiley, New York, 1998:p.147–159.

    Google Scholar 

  99. Ramanathan, M., MacGregor, R.D., Hunt, C.A. Predictions of effect for intracellular antisense oligodeoxyribonucleotides from akinetic model. Antisense Res. Dev. 1993; 3: 3–18.

    PubMed  CAS  Google Scholar 

  100. Goodchild, J., Carroll, E., III, and Greenberg, J.R. Inhibition of rabbit β-globin synthesis by complementary oligonucleotides: Identification of mRNA sites sensitive to inhibition. Arch. Biochem. Biophys. 1988; 263: 401–409.

    PubMed  CAS  Google Scholar 

  101. Wagner, R.W., Matteucci, M.D., Lewis, J.G. et al. Antisense gene inhibition by oligonucleotides containing C-5 propyne pyrimidines. Science. 1993; 260: 1510–1513.

    PubMed  CAS  Google Scholar 

  102. Maltese, J.-Y., Sharma, H.W., Vassilev, L., Narayanan, R. Sequence context of antisense RelA/NF-κB phosphorothioates determines specificity. Nucleic Acids Res. 1995; 23: 1146–1151.

    PubMed  CAS  Google Scholar 

  103. Stein, C.A. Phosphorothioate antisense oligodeoxynucleotides: questions of specificity. Trends in BioTechnology, 1996; 14: 147–149.

    PubMed  CAS  Google Scholar 

  104. Schwartz, R.S., Holmes, D.R., Topol, E.J. The restenosis paradigm revisted: an alternate proposal for cellular mechanisms. J. Amer. Coll. Cardiol. 1992; 20: 1984–1993.

    Google Scholar 

  105. Cohen, J. Oligonucleotides as therapeutic agents. Pharmacol. Ther. 1991; 52: 211–225.

    PubMed  CAS  Google Scholar 

  106. Colman, A. Antisense strategies in cell and development biology. J. Cell Sci. 1990; 97: 399–409.

    PubMed  CAS  Google Scholar 

  107. Pickering, G., Weir, L., Jekanowski, J.et al. Inhibition of proliferation of human vascular smooth muscle cells using antisense oligonucleotides to PCNA. J. Amer. Coll. Cardiol. 1992; 19: 165. Abstract.

    Google Scholar 

  108. Biro, S., Fu, Y.M., Yu, Z.X. et al. Inhibitory effects of antisense oligodeoxynucleotides targeting c-myc mRNA on smooth muscle cell proliferation and migration. Proc. Natl. Acad.Sci.U.S. A 1993; 90: 654–658.

    PubMed  CAS  Google Scholar 

  109. Simons, M., Rosenberg, R.D. Antisense nonmuscle myosin heavy chain and c-myb oligonucleotides suppress smooth muscle cell proliferation in vitro. Circ. Res.1992; 70: 835–843.

    PubMed  CAS  Google Scholar 

  110. Morishita, R., Gibbons, G.H., Ellison, K.E. et al. Intima] hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides. J. Clin. Invest. 1994; 93: 1458–1464.

    PubMed  CAS  Google Scholar 

  111. Gunn, J., Holt, C., Sheperd, L., Francis, S., Smith, G., Cumberland, D.Local delivery of c-myb antisense attenuates neo-intimal thickening in porcine model of coronary angioplasty. J. Amer. Coll. Cardiol. 1995; 25: 201A

    Google Scholar 

  112. Edelman, E., Simons, M., Sirois, M., Rosenberg, R. c-Myc in vasculoproliferative disease. Circ. Res.1995; 76: 176–182.

    PubMed  CAS  Google Scholar 

  113. Shi, Y., Fard, A., Galeo, A., et al. Transcatheter delivery of c-myc antisense oligomer reduces neointimal formation in a porcine model of coronary artery balloon injury. Circulation 1994; 90: 944–951.

    PubMed  CAS  Google Scholar 

  114. Abe, J., Zhou, W., Taguchi, J., et al. Suppression of neointimal smooth muscle cell accumulation in vivo by antisense cdc 2 and cdk 2 oligonucleotides in rat carotid artery. Biochem. Biophys. Res. Comm. 1994; 198: 16–24.

    PubMed  CAS  Google Scholar 

  115. Simons, M., Edelman, E.R., Rosenberg, R.D. Antisense proliferating cell nuclear antigen oligonucleotides inhibit intimai hyperplasia in a rat carotid artery injury model. J. Clin. Invest. 1994; 93: 2351–2356.

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA

    I. V. Lebedeva & C. A. Stein

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  1. I. V. Lebedeva
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  1. Cardiology Division, Columbia University College of Physicians and Surgeons, New York, NY, USA

    LeRoy E. Rabbani M.D. (Assistant Professor of Medicine) (Assistant Professor of Medicine)

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Lebedeva, I.V., Stein, C.A. (1999). Phosphorothioate Oligodeoxynucleotides as Inhibitors Of Gene Expression: Antisense and Non-Antisense Effects. In: Rabbani, L.E. (eds) Applications of Antisense Therapies to Restenosis. Perspectives in Antisense Science, vol 3. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5183-6_6

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  • DOI: https://doi.org/10.1007/978-1-4615-5183-6_6

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