Preclinical Development of Antisense Therapeutics

  • A. A. Levin
  • S. P. Henry
  • C. F. Bennett
  • D. L. Cole
  • G. E. Hardee
  • G. S. Srivatsa
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 137)


Phosphorothioate oligodeoxynucleotides appear to be an important new class of human therapeutic agents and are the first compounds shown to have the properties required of antisense drugs. They have well-demonstrated antisense modes of drug action, are stable in vitro and have very acceptable half-lives in vivo. When administered by injection, phosphorothioate oligodeoxynucleotides distribute rapidly to tissues and show excellent pharmacokinetics. To date, they have exhibited mild and manageable toxicities at projected and demonstrated therapeutic doses. Phosphorothioate oligodeoxynucleotides are readily taken up by cells in vivo without need for added uptake enhancers. At lengths of 20–21 nucleotides or less, they exhibit messenger RNA (mRNA) affinities sufficient to inhibit gene expression at doses which, in turn, can provide good therapeutic indices and acceptable cost to the patient.


Antisense Oligonucleotide Preclinical Development Antisense Oligodeoxynucleotide Hairless Mouse Skin Basophilic Granule 
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  1. Agrawal S (1992) Antisense oligonucleotides as antiviral agents. Trends Biotechnol: 152 - 158Google Scholar
  2. Agrawal S, Goodchild J, Civeira MP, Thornton AH, Sarin PS, Zamecnik PC (1988b) Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus. Proc Natl Acad Sci USA 85: 7079 – 7083CrossRefGoogle Scholar
  3. Agrawal S, Ikeuchi T, Sun D, Sarin PS, Konopka A, Maizel J, Zamecnik PC (1989) Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues. Proc Natl Acad Sci USA 86: 7790 – 7794PubMedCrossRefGoogle Scholar
  4. Agrawal S, Tang JT, Brown DM (1990) Analytical study of phosphorothioate analogues of oligodeoxynucleotides using high-performance liquid chromotography. J Chromatogr: 396 – 399Google Scholar
  5. Agrawal S, Temsamani J, Galbraith W, Tang J (1995b) Pharmacoketics of antisense oligonucleotides. Clin Pharmacokinet 28: 7 – 16CrossRefGoogle Scholar
  6. Agrawal S, Temsamani J, Tang JY (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynueleotide phosphorothioates in mice. Proc Natl Acad Sci USA 88: 7595 – 7599PubMedCrossRefGoogle Scholar
  7. Agrawal S, Zhang X, Lu Z, Zhao H, Tamburin JM, Yan J, Cai H, Diasio RG, Habus I, Jiang Z, Iyer RP, Yu D, Zhang R (1995a) Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration. Biochem Pharmacol 50: 571 – 576CrossRefGoogle Scholar
  8. Agrawal S, Temsamani J, Galbraith W, Tang J (1995b) Pharmacokinetics of antisense oligonucleotides. Clin Pharmacokinet 28: 7 – 16CrossRefGoogle Scholar
  9. Anderson KP, Driver VB, Fox MC, Martin M, Azad RF (1996) Inhibition of cytomegalovirus immediate early gene expression by an antisense oligonucleotide complementary to immediate early RNA. Antimicrob Agents ChemotherGoogle Scholar
  10. Azad RF, Driver VB, Tanaka K, Crooke RM, Anderson KP (1993) Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region. Antimicrob Agents Chemother 37: 1945 – 1954PubMedGoogle Scholar
  11. Azad RF, Driver VB, Buckheit R Jr, Anderson KP (1995) Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs. Antiviral Res 28: 101 – 111PubMedCrossRefGoogle Scholar
  12. Bennett CF, Chiang M-Y, Chan H, Shoemaker JEE, Mirabelli CK (1992) Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Mol Pharmacol 41: 1023 – 1033PubMedGoogle Scholar
  13. Bennett CF, Chiang M-Y, Wilson-Lingardo L, Wyatt JR (1994) Sequence specific inhibition of human type II phospholipase A2 enzyme activity by phosphorothioate oligonucleotides. Nucleic Acids Res 22: 3202 – 3209PubMedCrossRefGoogle Scholar
  14. Bennett CF, Condon T, Grimm S, Chan H, Chiang MY (1995) Inhibition of endothelial cell-leukocyte adhesion molecule expression with antisense oligonucleotides. J Immunol 152: 3530 – 3540Google Scholar
  15. Bennett CF, Kornbrust DJ, Henry SP, Stecker K, Howard R, Cooper S, Dutson S, Hall W, Jacoby HI (1997) An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice. J Pharmacol Exp Ther 280: 988 – 1000PubMedGoogle Scholar
  16. Bennett RM, Gabor GT, Merritt MM (1985) DNA binding to human leukocytes. Am Soc Clin Invest 76: 2182 – 2190CrossRefGoogle Scholar
  17. Bergot BJ, Egan W (1992) Separation of synthetic phosphorothioate oligodeoxy- nucleotides from their oxygenated (phosphodiester) defect species by strong- anion-exchange high-performance liquid chromatography. J Chromatogr: 35 – 42Google Scholar
  18. Bock LC, Griffin LC, Latham JA, Vermaas EH, Toole JJ (1992) Selection of single stranded DNA molecules that bind and inhibit human thrombin. Nature 355: 564 – 566PubMedCrossRefGoogle Scholar
  19. Boman NL, Bally M.B, Cullis PR, Mayer LD, Webb MS (1995) Encapsulation of vincristine in liposomes reduces its toxicity and improves its anti-tumor efficacy. J Lipid Res 5: 523 – 541Google Scholar
  20. Boussif O, Lezoualc’h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, Behr J- P (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc Natl Acad Sci USA 92: 7297 – 7301PubMedCrossRefGoogle Scholar
  21. Branda RF, Moore AL, Mathews L, McCormack JJ, Zon G (1993) Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1. Biochem Pharmacol 45: 2037 – 2043PubMedCrossRefGoogle Scholar
  22. Carlson RH, Bozick AH, Fitchett JR (1994) Comparison of the accuracy and precision between capillary gel electrophoresis versus Polyacrylamide gel electrophoresis for assay and impurity determinations of pharmsceutical polynucleotide samples. In Sixth International Symposium on Capillary Electrophoresis, San Diego, CA, USAGoogle Scholar
  23. Chiang MY, Chan H, Zounes MA, Freier SM, Lima WF, Bennett CF (1991) Antisense oligonucleotides inhibit intercellular adhesion molecular 1 expression by two distinct mechanisms. J Biol Chem 266: 18162 – 18171PubMedGoogle Scholar
  24. Chiasson BJ, Hooper ML, Murphy PR, Robertson HA (1992) Antisense oligonucleotide eliminates in vivo expression of c-fos in mammalian brian. Eur J Pharmacol 227: 451 – 453PubMedCrossRefGoogle Scholar
  25. Cohen AS, Vilenchik M, Dudley JL, Gemborys MW, Bourque AJ (1993) High-performance liquid chromatography and capillary gel electrophoresis as applied to antisense DNA. J Chromatogr: 293 – 301Google Scholar
  26. Cornish KG, Iversen P, Smith L, Arneson M, Bayever E (1993) Cardiovascular effects of a phosporothioate oligonucleotide with sequence antisense to p53 in the conscious rhesus monkey. Pharmacol Commun 3: 239 – 247Google Scholar
  27. Cossum PA, Sasmor H, Dellinger D, Troung L, Cummins L, Owens SR, Markham PM, Shea JP, Crooke S (1993) Disposition of the 14c-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. J Pharmacol Exp Ther 267: 1181 – 1190PubMedGoogle Scholar
  28. Cossum PA, Troung L, Owens SR, Markham PM, Shea JP, Crooke ST (1994) Pharmacokinetics of a 14c-labeled phosphorothioate oligonucleotide, ISIS 2105, after intradermal administration to rats. J Pharmacol Exp Ther 269: 89 – 94PubMedGoogle Scholar
  29. Crooke ST, Bennett CF (1996a) Progress in antisense oligonucleotide therapeutics.Annu Rev Pharmacol Toxicol 36: 107 – 129Google Scholar
  30. Crooke ST, Graham MJ, Zuckerman JE, Brooks D, Conklin BS, Cummins LL, Greig MJ, Guinosso CJ, Kornbrust D, Manoharan M, Sasmor HM, Schleich T, Tivel KL, Griffey RH (1996b) Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J Pharmacol Exp Ther 277: 923 – 937Google Scholar
  31. Dean NM, McKay R (1994) Inhibition of PKC-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc Natl Acad Sci USA 91: 11762 – 11766PubMedCrossRefGoogle Scholar
  32. Dean NM, McKay R, Condon TP, Bennett CF (1994) Inhibition of protein kinase C-alpha expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J Biol Chem 269: 16416 – 16424PubMedGoogle Scholar
  33. Diamantstein T, Blistein-Willinger E (1978) Specific binding of poly (I) - poly (C) to the membrane of murine B lymphocyte subsets. Eur J Immunol 8: 896 – 899PubMedCrossRefGoogle Scholar
  34. Diamantstein T, Wagner B, Beyse I, Odenwald MV, Schultz G (1971) Stimulation of humoral antibody formation by poly anions. I. The effect of poly aery lie acid on the primary immune response in mice immunized with sheep red blood cells. Eur J Immunol 1: 335 – 340PubMedCrossRefGoogle Scholar
  35. Feldman MA, Parsons JM, Lee JA, Srivatsa GS (1995) The inhibition effect of phosphorothioate oligonucleotides on the LAL test is reduced through the CaCl2 precipitation of the oligonucleotides. In Sixth International Symposium on Pharmaceutical and Biomedical Analysis, St. Louis, MO, USAGoogle Scholar
  36. Felgner PL, Kumar R, Basava C, Border RC, Hwang-Feigner J-Y (1995) Cationic lipids for intracellular delivery of biologically active molecules. In United States Patent Office. USAGoogle Scholar
  37. Fuhrman LC, Ocheltree TW, Godwin DA, Michniak BB, Bennett CF (1995) Evaluation of several liposomal formulations and preparation techniques for the dermal delivery of phosphorothioate antisense oligonucleotides in hairless mouse skin in vitro. In AAPS Annual Meeting. Miami Beach, FL, USAGoogle Scholar
  38. Galbraith WM, Hobson WC, Giclas PC, Schechter PJ, Agrawal S (1994) Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res Dev 4: 201 – 206PubMedGoogle Scholar
  39. Geary RS, Leeds JM, Fitchett J, Burckin T, Truong L, Spainhour C, Creek M, Levin AA (1997) Pharmacokinetics and metabolism in mice of a phosphorothioate oligonucleotide antisense inhibitor of C-raf-Kinase expression. Drug Metab Dispos 25: 1212 – 1281Google Scholar
  40. Glover JM, Leeds JM, Mant TGK, Amin D, Kisner DL, Zuckerman J, Levin A A, Shanahan WR (1997) Phase 1 safety and pharmacokinetic profile of an ICAM-1 antisense oligodeoxynucleotide (ISIS 2302). J Pharmacol Exp Ther 282: 1173 – 1180PubMedGoogle Scholar
  41. Henry SP, Larkin R, Novotny WF, Kornbrust DJ (1994) Effects of ISIS 2302, a phosphorothioate oligonucleotide, on in vitro and in vivo coagulation parameters. Pharm Res II:S–353Google Scholar
  42. Henry SP, Leeds J, Giclas PC, Gillett NA, Pribble JP, Kornbrust DJ, Levin AA (1996) The toxicity of ISIS 3521, a phosphorothioate oligonucleotide, following intravenous (IV) and subcutaneous (SC) administration in cynomolgus monkeys. Toxicol 30: 112Google Scholar
  43. Henry SP, Monteith DK, Levin AA (1997a) Antisense oligonucleotide inhibitors for the treatment of cancer: (2). Toxicological properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des 12: 395 – 408Google Scholar
  44. Henry SP, Taylor J, Midgley L, Levin AA, Kornbrust DJ (1997b) Evaluation of the toxicity of ISIS 2302 a phosphorothioate oligonucleotide, in a 4 week study in CS- 1 mice. Antisense Nucleic Acid Drug Dev 7: 473 – 481Google Scholar
  45. Hooper ML, Chiasson BJ, Robertson HA (1994) Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of fos and produces a behavioral effect. Neuroscience: 917 – 924Google Scholar
  46. Iversen P (1991) In vivo studies with phosphorothioate oligonucleotides: pharmacokinetics prologue. Anticancer Drug Des 6: 531 – 538PubMedGoogle Scholar
  47. Kambhampati RVB, Chiu Y-Y, Chen CW, Blumenstein JL (1993) Regulatory concerns for the chemistry, manufacturing, and controls of oligonucleotides for use in clinical studies. Antisense Res Dev 3: 405 – 410PubMedGoogle Scholar
  48. Katz SM, Browne B, Pham T, Wang ME, Bennett CF, Stepkowski SM, Kahan BD (1995) Efficacy of ICAM-1 antisense oligonucleotide in pancreatic islet transplantation. Transplant Proc 27: 3214PubMedGoogle Scholar
  49. Klinman DM, AE-Kyung Y, Beaucage SL, Conover J, Krieg AM (1996) CpG motifs present in bacterial DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon γ. Proc Natl Acad Sci USA 93: 2879 – 2883PubMedCrossRefGoogle Scholar
  50. Krieg AM, Yi A-K, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374: 546 – 549PubMedCrossRefGoogle Scholar
  51. Kumasaka T, Quinlan WM, Doyle NA, Condon TP, Sligh J, Takei F, Beaudet AL, Bennett CF, Doerschuk CM (1996) The role of ICAM-1 in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice. J Clin InvestGoogle Scholar
  52. Lasic DD, Needham D (1995) The “stealth” liposome: a prototypical biomaterial. Chem Rev 95: 2601 – 2628CrossRefGoogle Scholar
  53. Lee K-D, Oh YK, Portnoy DA, Swanson JA (1996) Delivery of macromolecules into cytosol using liposomes containing hemolysin from listeria monocytogenes. J of Biol Chem 271: 7249 – 7252CrossRefGoogle Scholar
  54. Leeds JM, Graham MJ, Truong L, Cummins LL (1996b) Quantitation of phosphorothioate oligonucleotides in human plasma. Anal Biochem 235: 36 – 43CrossRefGoogle Scholar
  55. Leeds JM, Williams K, Scherrill S, Levin AA, Bistner S, Henry SP (1996a) Potential for retinal accumulation of a phosphorothioate oligonucleotide (ISIS 2922) after intravitreal injection in cynomolgus monkeys. In Society of Toxicology Annual Meeting. Anaheim, CA, USAGoogle Scholar
  56. Lewis JG, Lin K-Y, Kothavale A, Flanagan WM, Matteucci MD (1996) A serum- resistant cytofectin for cellular delivery of antisense oligodeoxynucleotides and plasmid DNA. Proc Natl Acad Sci USA 93: 3176 – 3181PubMedCrossRefGoogle Scholar
  57. Lisziewicz J, Sun D, Metelev V, Zamecnik P, Gallo RC, Agrawal S (1993) Long-term treatment of human immunodeficiency virus-infected cells with anstisense oligonucleotide phosphorothioates. Proc Natl Acad Sci USA 30: 3860 – 3864CrossRefGoogle Scholar
  58. Mclntyre KW, Lombard-Gillooly K, Perez JR, Kunsch C, Sarmiento UM, Larigan JD, Landreth KT, Narayanan R (1993) A sense phosphorothioate oligonucleotide directed to the initiation codon of transcription factor nf-kb p65 causes sequence- specific immune stimulation. Antisense Res Dev 3: 309 – 322Google Scholar
  59. Monia BP, Johnston JF, Ecker DJ, Zounes MA, Lima WF, Freier SM (1992) Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem 267: 19954 – 19962PubMedGoogle Scholar
  60. Nestle FO, Mitra RS, Bennett CF, Chan H, Nickoloff BJ (1994) Cationic lipid is not required for uptake and selective inhibitory activity of ICAM-1 phosphorothioate antisense oligonucleotides in keratinocytes. J Invest Dermatol 103: 569 – 575PubMedCrossRefGoogle Scholar
  61. Oberbauer R, Schreiner GF, Meyer TW (1995) Renal uptake of an 18-mer phosphorothioate oligonucleotide. Kidney Int 48: 1226 – 1232PubMedCrossRefGoogle Scholar
  62. Ocheltree TW, Fuhrman LC, Mehta R, Michniak BB, Shah JC (1996) Epidermal and dermal penetration of anionic and zwitterionic liposomally encapsulated antisense oligonucleotides into hairless mouse skin. In Amer Assoc of Pharm Scientists, ed. R. Mehta. Seattle, WA, USAGoogle Scholar
  63. Plenat F, Klein-Monhoven N, Marie B, Vignaud J-M, Duprez A (1994) Cell and tissue distribution of synthetic oligonucleotides in healthy and tumor-bearing nude mice. Am J Pathol 147: 124 – 135Google Scholar
  64. Rappaport J, Hanss B, Kopp JB, Copeland TD, Bruggeman LA, Coffman TM, Klotman PE (1995) Transport of phosphorothioate oligonucleotides in kidney implications for molecular therapy. Kidney Int 47: 1462 – 1469PubMedCrossRefGoogle Scholar
  65. Ravikumar VT, Andrade M, Wyrzykiewicz TK, Scozzari A, Cole DL (1995) Large- scale synthesis of oligodeoxyribonucleotide phosphorothioate using controlled- pore glass as support. Nucleosides Nucleotides 14: 1219 – 1226CrossRefGoogle Scholar
  66. Rosenberger RD (1989) Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 87:2S–3SGoogle Scholar
  67. Saijo Y, Perlaky L, Wang H, Busch H (1994) Pharmacokinetics, tissue distribution, and stability of antisense oligodeoxynucleotide phosphorothioate ISIS 3466 in mice. Oncol Res 6: 243 – 249PubMedGoogle Scholar
  68. Sands H, Gorey-Feret LJ, Cocuzza AJ, Hobbs FW, Chidester D, Trainor GL (1994) Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and phosphorothioate. Mol Pharmacol 45: 932 – 943PubMedGoogle Scholar
  69. Sarmiento UM, Perez JR, Becker JM, Narayanan R (1994) In vivo toxicological effects of rei A antisense phosphorothioates in CD-1 mice. Antisense Res Dev 4: 99 – 107PubMedGoogle Scholar
  70. Sawai K, Miyao T, Takakura Y, Hashida M (1995) Renal disposition characteristics of oligonucleotides modified at terminal linkages in the perfused rat kidney. Antisense Res Dev 5: 279 – 287PubMedGoogle Scholar
  71. Schuette J, Srivatsa GS, Cole DL (1994) Development and validation of a method for routine base composition analysis of phosphorothioate oligonucleotides. J Pharm Biomed Anal 12: 1345 – 1353PubMedCrossRefGoogle Scholar
  72. Schuette J, Pieles U, Maleknia S, Srivatsa GS, Cole DL, Moser HE, Afeyan NB (1995) Sequence analysis of phosphorothioate oligonucleotides via matrix-assisted laser desorption ionization time-of-flight mass spectrometry. J Pharm Biomed Anal 13: 1195 – 1203PubMedCrossRefGoogle Scholar
  73. Srinivasan SK, Iversen P (1995) Review of in vivo pharmacokinetics and toxicology of piiosphorothioate oligonucleotides. J Clin Lab Anal 9: 129 – 137PubMedCrossRefGoogle Scholar
  74. Srivatsa GS, Batt M, Schuette J, Carlson R, Fitchett J, Lee C, Cole DL (1994) Quantitative capillary gel electrophoresis (QCGE) assay of phosphorothioate oligonucleotide in pharmaceutical formulations. J Chromatogr 680: 469 – 477CrossRefGoogle Scholar
  75. Srivatsa GS, Klopehin P, Batt M, Feldman M, Carlson RH, Cole DL (1997) Selectivity of anion exchange chromatography and capillary gel electrophoresis for the analysis of phosphorothioate oligonucleotides. J Pharm Biomed Anal 16: 619 – 630PubMedCrossRefGoogle Scholar
  76. Stein CA (1995) Does antisense exist? Nat Med 1: 1119 – 1121PubMedCrossRefGoogle Scholar
  77. Stein CA, Cheng Y-C (1993) Antisense oligonucleotides as therapeutic agents-Is the bullet really magical? Science 261: 1004 – 1012PubMedCrossRefGoogle Scholar
  78. Stein CA, Krieg AM (1994) Problems in intrepretation of data derived from in vitro and in vivo use of antisense oligodeoxynucleotides. Antisense Res Dev 4: 67 – 69PubMedGoogle Scholar
  79. Stein CA, Neckers M, Nair BC, Mumbauer S, Hoke G, Pal R (1991) Phosphorothioate oligodeoxycytidine interferes with binding of HIV-1 gp120 to CD4. J Acquir Immune Defic Syndr 4: 686 – 693PubMedGoogle Scholar
  80. Stepkowski SM, Tu Y, Condon TP, Bennett CF (1994) Blocking of heart allograft rejection by intercellular adhesion molecule-1 antisense oligonucleotides alone or in combination with other immunosuppresive modalities. J Immunol 10: 5336 – 5346Google Scholar
  81. Suska A, Grajkowski A, Wilk A, Uznanski B, Blaszczyk J, Wieczorek M, Stec WJ (1993) Antisense oligonucleotides: Stereocontrolled synthesis of phosphoro¬thioate oligonucleotides. Pure Appi Chem 65: 707 – 714CrossRefGoogle Scholar
  82. Szklarczyk A, Kaczmarek L (1995) Antisense oligodeoxyribonucleotides: Stability and distribution after intracerebral injection into rat brain. J Neurosci Methods: 181 – 187Google Scholar
  83. Talmadge JE, Adams J, Phillips H, Collins M, Lenz B, Schneider M, Schlick E, Ruffmann R, Wiltrout RH, Chirigos MA (1985) Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymenthycellulosel. Cancer Res 45: 1058 – 1065PubMedGoogle Scholar
  84. Temsamani J, Tang J-Y, Padmapriya A, Kubert M, Agrawal S (1993) Pharmacokinetics, biodistribution, and stability of capped oligodeoxynucleotide phosphoro- thioates in mice. Antisense Research and Development 3: 277 – 284PubMedGoogle Scholar
  85. Warren WJ, Velia G (1993) Analysis of synthetic oligodeoxyribonucleotides by capillary gel electrophoresis and anion-exchange HPLC. BioTechniques 14: 598 – 606PubMedGoogle Scholar
  86. Watson PH, Pon RT, Shiu RPC (1992) Inhibition of cell adhesion to plastic substratum by phosphorothioate oligonucleotide. Exp Cell Res 202: 391 – 397PubMedCrossRefGoogle Scholar
  87. Weiss B, Zhou L-W, Zhang S-P, Qin Z-H (1993) Antisense oligodeoxynucleotide inhibits D2 dopamine receptor-mediated behavior and D2 messanger RNA. Neuroscience 55: 607 – 612PubMedCrossRefGoogle Scholar
  88. Whitesell L, Geselowitz D, Chavany C, Fahmy B, Walbridge S, Alger JR, Neckers LM (1993) Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system. Proc Natl Acad Sci USA 90: 4665 – 4669PubMedCrossRefGoogle Scholar
  89. Wu-Pong S, Weiss TL, Hunt AC (1994) Antisense c-mycoligonucleotide cellular uptake and activity. Antisense Res Dev 4: 155 – 163PubMedGoogle Scholar
  90. Wyrzykiewicz TK, Cole DL (1994) Sequencing of oligonucleotide phosphorothioates based on solid-supported desulfurization. Nucleic Acids Res 22: 2667 – 2669PubMedCrossRefGoogle Scholar
  91. Wyrzykiewicz TK, Cole DL (1995) Stereo-reproducibility of the phosphoramidite method in the synthesis of oligonucleotide phosphorothioates. Bioorg Chem 23: 33 – 41CrossRefGoogle Scholar
  92. Yamamoto T, Yamamoto S, Kataoka T, Tokunaga T (1994) Ability of oligonucleotides with certain palindromes to induce interferon production and augment natural killer cell activity is associated with their base length. Antisense Res Dev: 119 – 122Google Scholar
  93. Yazaki T, Ahmad S, Chahlavi A, Zylber-Katz E, Dean NM, Martuza RL, RI G (1996Submitted) Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxy nucleo tide. Mol Pharmacol 50:236–242Google Scholar
  94. Zhou L-W, Zhang S-P, Qin Z-H, Weiss B (1994) In vivo administration of an oligodeoxynucleotide antisense to the D2 dopamine receptors in mouse striatum. J Pharmacol Exp Ther 268: 1015 – 1023PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • A. A. Levin
  • S. P. Henry
  • C. F. Bennett
  • D. L. Cole
  • G. E. Hardee
  • G. S. Srivatsa

There are no affiliations available

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