Skip to main content
SpringerLink
Log in

Toxicity of Oligodeoxynucleotide Therapeutic Agents

  • Chapter
Antisense Research and Application

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 131))

Abstract

One of the most exciting aspects of antisense therapeutic agents is their remarkable pharmacologic specificity. Because antisense activity depends on Watson and Crick base-pairing rules, sequence specificity ensures that antisense agents have high selectivity for the intended mRNA target. The selective inhibition of the expression of disease-related genes is the pharmacologic equivalent of laser surgery, well aimed and presumably with minimal inadvertent effects. This specificity suggests that these agents will have favorable therapeutic indices.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 429.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 549.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Agrawal S, Temsamani J, Tang JY (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci USA 88:7595–7599

    Article  PubMed  CAS  Google Scholar 

  • Agrawal S, Rustagi P, Shaw DR (1995a) Novel enzymatic and immunological responses to oligonucleotides. In: Reed DJ (ed) Proceedings of the international congress of toxicology VII. Elsevier, Amsterdam, pp 431–434

    Google Scholar 

  • 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 (1995b) Absorption, tissue distribution and in vivo stability in rats of a hybrid antisense oligonucleotide following oral administration. Biochem Pharmacol 50:571–576

    Article  CAS  Google Scholar 

  • Altmann K-H, Dean NM, Fabbro D, Freier SM, Geiger T, Haner R, Husken D, Martin P, Monia BP, Muller M, Natt F, Nicklin P, Phillips J, Pieles U, Sasmor H, Moser HE (1996) Second generation of antisense oligonucleotides: from nuclease resistance to biological efficant in animals. Chimia 50:168–176

    CAS  Google Scholar 

  • Anderson KP, Fox MC, Brown-Driver V, Martin MJ, Azad RF (1996) Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemother 40:2004–2011

    PubMed  CAS  Google Scholar 

  • Augustine KA, Liu ET, Sadler TW (1995) Antisense inhibition of engrailed genes in mouse embryos reveals roles for these genes in craniofacial and neural tube development. Teratology 51:300–310

    Article  PubMed  CAS  Google Scholar 

  • Bavik C, Ward SJ, Chambon P (1996) Developmental abnormalities in cultured mouse embryos deprived of retinoic acid by inhibition of yolk-sac retinol binding protein synthesis. Proc Natl Acad Sci USA 93:3110–3114

    Article  PubMed  CAS  Google Scholar 

  • Bennett CF (1994) Inhibition of cell adhesion molecule expression with antisense oligonucleotides: activity in-vitro and in-vivo. J Immunol 152:3530–3540

    PubMed  CAS  Google Scholar 

  • 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 41:1023–1033

    PubMed  CAS  Google Scholar 

  • Bennett CF, Dean N, Ecker DJ, Monia BP (1996) Pharmacology of antisense therapeutic agents: cancer and inflammation. In: Agrawal S (ed) Methods in molecular medicine: antisense therapeutics. Humana, Totowa, New York, pp 13–46

    Google Scholar 

  • Bennett CF, Kornbrust D, Henry S, 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 280:988–1000

    PubMed  CAS  Google Scholar 

  • Bennett RM, Gabor GT, Merritt MM (1985) DNA binding to human leukocytes. J Clin Invest 76:2182–2190

    Article  PubMed  CAS  Google Scholar 

  • Bitter-Suermann D, Burger R, Hadding U (1981) Activation of the alternative pathway of complement: efficient fluid-phase amplification by blockade of the regulatory complement protein bl h through sulfated polyanions. Eur J Immunol 11:291–295

    Article  PubMed  CAS  Google Scholar 

  • Black LE, DeGeorge JJ, Cavagnaro JA, Jordan A, Ahn C-H (1993) Regulatory considerations for evaluating the pharmacology and toxicology of antisense drugs. Antisense Res Dev 3:399–404

    PubMed  CAS  Google Scholar 

  • Black LE, Farrelly JG, Cavagnaro JA, Ahn C-H, DeGeorge JJ, Taylor AS, DeFelice AF, Jordan A (1994) Regulatory considerations of oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies. Antisense Res Dev 4:299–301

    PubMed  CAS  Google Scholar 

  • 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 45:2037–2043

    Article  PubMed  CAS  Google Scholar 

  • Branda RF, Moore AL, Lafayette AR, Mathews L, Hong R, Zon G, Brown T, McCormack JJ (1996) Amplification of antibody production by phosphorothioate oligodeoxynucleotides. J Lab Clin Med 128:329–338

    Article  CAS  Google Scholar 

  • Brown DA, Kang S-H, Gryaznov SM, DeDionisio L, Heidenreich O, Sullivan S, Xu X, Nerenberg MI (1994) Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem 269:26801–26805

    PubMed  CAS  Google Scholar 

  • Butler M, Stecker K, Bennett CF (1997) Histologic localization of phosphorothioate deoxyoligonucleotides in normal rat tissues. Lab Invest 77(4):379–388

    PubMed  CAS  Google Scholar 

  • Chiang M-Y, Chan H, Zounes MA, Freier SM, Lima WF, Bennett CF (1991) Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J Biol Chem 266:18162–18171

    PubMed  CAS  Google Scholar 

  • Cornish KG, Iversen P, Smith L, Arneson M, Bayever E (1993) Cardiovascular effects of a phosphorothioate oligonucleotide with sequence antisense to p53 in the conscious rhesus monkey. Pharmacol Commun 3:239–247

    CAS  Google Scholar 

  • 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 267:1181–1190

    PubMed  CAS  Google Scholar 

  • 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 269:89–94

    PubMed  CAS  Google Scholar 

  • Crooke RM, Crooke ST, Graham MJ, Cooke ME (1996) Effect of antisense oligonucleotides on cytokine release from human keratinocytes in an in vitro model of skin. Toxicol Appl Pharmacol 140:85–93

    Article  PubMed  CAS  Google Scholar 

  • Cummins LL, Leeds JM, Greig M, Griffey RJ, Graham MJ, Crooke R, Gaus HJ (1997) Capillary gel electrophoresis and mass spectrometry: powerful tools for the analysis of antisense oligonucleotides and their metabolites. In: Cook PD, Manoharan M (eds) Nucleosides and nucleotides. Marcel Decker, New York (in press)

    Google Scholar 

  • Dean NM, McKay R, Condon TP, Bennett CF (1994) Inhibition of protein kinase C-a expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J Biol Chem 269:16416–16424

    PubMed  CAS  Google Scholar 

  • de Serres M, McNulty MJ, Christensen L, Zon G, Findlay JWA (1996) Development of a novel scintillation proximity competitive hybridization assay for the determination of phosphorothioate antisense oligonucleotide plasma concentrations in a toxicokinetic study. Anal Biochem 233:228–233

    Article  PubMed  Google Scholar 

  • Diamantstein T, Blistein-Willinger E (1978) Specific binding of poly (I)-poly (C) to the membrane of murine B lymphocyte subsets. Eur J Immunol 8:896–899

    Article  PubMed  CAS  Google Scholar 

  • Diamantstein T, Wagner B, Beyse I, Odenwald MV, Schultz G (1971a) Stimulation of humoral antibody formation by polyanions. I. The effect of polyacrylic acid on the primary immune response in mice immunized with sheep red blood cells. Eur J Immunol 1:335–340

    Article  CAS  Google Scholar 

  • Diamantstein T, Wagner B, Beyse I, Odenwald MV, Schultz G (1971b) Stimulation of humoral antibody formation by polyanions. II. The influence of sulfate esters of polymers on the immune response in mice. Eur J Immunol 1:340–343

    Article  CAS  Google Scholar 

  • 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 4:201–206

    PubMed  CAS  Google Scholar 

  • Gaudette MF, Hampikian G, Metelev V, Agrawal S, Crain W (1993) Effect on embryos of injection of phosphorothioate-modified oligonucleotides into pregnant mice. Antisense Res Dev 3:391–397

    PubMed  CAS  Google Scholar 

  • Geary R, Leeds J, Henry SP, Monteith DK, Levin AA (1997) Antisense oligonucleotide inhibitors for the treatment of cancer. 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anti Cancer Drug Des 12:383–393

    CAS  Google Scholar 

  • Glover JM, Leeds JM, Mant TGK, Amin D, Kisner DL, Zuckerman J, Levin AA, Shanahan WR (1997) Phase 1 safety and pharmacokinetic profile of an ICAM-1 antisense oligodeoxynucleotide (ISIS 2302). J Pharmacol Exp Ther 282:1173–1180

    PubMed  CAS  Google Scholar 

  • Griffin LC, Tidmarsh GF, Bock LC, Toole JJ, Leung LLK (1993) In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal circuits. Blood 81:3271–3276

    PubMed  CAS  Google Scholar 

  • Henry SP, Larkin R, Novotny WF, Kornbrust DJ (1994) Effects of ISIS 2302, a phosphorothioate oligonucleotide, on in vitro and in vivo coagulation parameters. Pharmaceut Res 11:S-353

    Google Scholar 

  • 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 (se) administration in cynomolgus monkeys. Toxicologist 30:112

    Google Scholar 

  • Henry SP, Bolte H, Auletta C, Kornbrust DJ (1997a) Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in cynomolgus monkeys. Toxicology 120:145–155

    Article  CAS  Google Scholar 

  • Henry SP, Giclas PC, Leeds J, Pangborn M, Auletta C, Levin AA, Kornbrust DJ (1997b) Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther 281:810–816

    CAS  Google Scholar 

  • Henry SP, Monteith DK, Bennett CF, Levin AA (1997c) Toxicologic and pharmacokinetic parameters of chemically modified antisense oligonucleotide inhibitors of PKC-alpha and C-raf kinase. Anti Cancer Drug Des 12:409–420

    CAS  Google Scholar 

  • Henry SP, Monteith DK, Levin AA (1997d) Antisense oligonucleotide inhibitors for treatment of cancer. 2. Toxicologic properties of phosphorothioate oligodeoxynucleotides. Anti Cancer Drug Des 12:395–408

    CAS  Google Scholar 

  • Henry SP, Taylor J, Midgley L, Levin AA, Kornbrust DL (1997e) Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-1 mice. Antisense Nucleic Acid Drug Dev 7:473–481

    Article  CAS  Google Scholar 

  • Henry SP, Novotny W, Leeds J, Auletta C, Kornbrust DJ (1997f) Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev 7:503–510

    Article  CAS  Google Scholar 

  • Henry SP, Orr JL, Brunner RH, Kornbrust DJ (1997g) Comparison of the toxicity profiles of ISIS 1082 and ISIS 2105, phosphorothioate oligonucleotides, following subacute intradermal administration in Sprague-Dawley rats. Toxicology 116:77–88

    Article  CAS  Google Scholar 

  • Homer MJ, Monteith DK, Gillett NA, Butler M, Henry SP, Bennett CF, Levin AA (1997) Evaluation of the renal effects of phosphorothioate oligonucleotides in monkeys. Fundam Appl Toxico 136:147

    Google Scholar 

  • Iversen P (1991) In vivo studies with phosphorothioate oligonucleotides: pharmacokinetics prologue. Anti Cancer Drug Des 6:531–538

    CAS  Google Scholar 

  • 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 g. Proc Natl Acad Sci USA 93:2879–2883

    Article  PubMed  CAS  Google Scholar 

  • Krieg AM, Stein CA (1995) Phosphorothioate oligodeoxynucleotides: antisense or anti-protein? Antisense Res Dev 5:241

    PubMed  CAS  Google Scholar 

  • 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 374:546–549

    Article  PubMed  CAS  Google Scholar 

  • Leeds JM, Kiorpes A, Geary RS, Henry SP, Goldensoph C, Levin AA (1996a) Single dose subcutaneous bioavailability of ISIS 2302, a phosphorothioate oligonucleotide. In: Research P (ed) Cynomolgus monkeys, vol 13. Plenum, Seattle, p S395

    Google Scholar 

  • Leeds JM, Williams K, Scherrill S, Levin AA, Bistner S, Henry SP (1996b) Potential for retinal accumulation of a phosphorothioate oligonucleotide (ISIS 2922) after intravitreal injection in cynomolgus monkeys. Fundam Appl Toxicol 30:40

    Google Scholar 

  • Leeds JM, Geary RS, Henry SP, Glover J, Shanahan W, Fitchett J, Burckin T, Truong L, Levin AA (1997a) Pharmacokinetic properties of phosphorothioate oligonucle-otides. In: Cook PD, Manoharan M (eds) Nucleosides and nucleotides. Marcel Decker, New York 16(7–9):1689–1693

    Google Scholar 

  • Leeds JM, Henry SP, Truong L, Zutsi A, Levin AA, Douglas KJ (1997b) Pharmacokinetics of a potential human cytomegalovirus therapeutic, A phosphorothioate oligonucleotide after intravitreal injection in the rabbit. Drug Metab Dispos 25(8):921–926

    CAS  Google Scholar 

  • Liang H, Nishioka Y, Reich CF, Pisetsky DS, Lipsky PE (1996a) Activation of human B cells by phosphorothioate oligodeoxynucleotides. J Clin Invest 98:1119–1129

    Article  CAS  Google Scholar 

  • Liang WW, Shi X, Deshpande D, Malanga CJ, Rojanasakul Y (1996b) Oligonucleotide targeting to alveolar macrophages by mannose. Biochim Biophys Acta 1279:227–234

    Article  Google Scholar 

  • Lieberman R, Boyer D, Terry B, Antoszyk A, Park S, Cantrill H, Ai E, Holland G, Palestine A. (submitted) Antisense oligonucleotide dose response for treatment of cytomegalovirus retinitis. Am J Ophthal

    Google Scholar 

  • Manza LL, Butler MM, Bennett CF, Levin AA, de Peyster AA, Monteith DK (1997) Renal toxicity of phosphorothioate oligonucleotides in rats. Fundam Appl Toxicol 36:147

    Google Scholar 

  • McIntyre 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 3:309–322

    PubMed  CAS  Google Scholar 

  • Miraglia L, Geiger T, Bennett CF, Dean N (1996) Inhibition of interleukin-1 type receptor expression in human cell-lines by an antisense phosphorothioate oligonucleotide. Int J Immunopharmacol 18:227–240

    Article  PubMed  CAS  Google Scholar 

  • Monia BP, Johnston JF, Ecker DJ, Zounes M, Lima WF, Freier SM (1992) Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem 267:19954–19962

    PubMed  CAS  Google Scholar 

  • Monia BP, Johnston JF, Geiger T, Muller M, Fabbro D (1995) Antitumor activity of a phosphorothioate oligodeoxynucleotide targeted against C-raf kinase. Nature Med 2:668–675

    Google Scholar 

  • Monia BP, Sasmor H, Johnston JF, Freier SM, Lesnik EA, Muller M, Geiger T, Altmann K-H, Moser H, Fabbro D (1996) Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human c-raf kinase supports an antisense mechanism of action in vivo. Proc Natl Acad Sci USA 93:15481–15484

    Article  PubMed  CAS  Google Scholar 

  • Monteith DK, Henry SP, Howard RB, Flournoy S, Levin AA, Bennett CF, Crooke ST (1997) Immune stimulation — a class effect of phosphorothioate oligonucleotides in rodents. Anti Cancer Drug Des 12:421–432

    CAS  Google Scholar 

  • Nicklin PL, Ambler J, Mitchelson A, Bayley D, Phillips JA, Craig SJ, Monia BP (1997) Preclinical profiling of modified oligonucleotides: anticoagulant and pharmacokinetic properties. In: Cook PD, Manoharan M (eds) Nucleosides and nucleotides. Marcel Decker, New York 16(7–9):1145–1153

    Google Scholar 

  • Oberbauer R, Schreiner GF, Meyer TW (1995) Renal uptake of an 18-mer phosphorothioate oligonucleotide. Kidney Int 48:1226–1232

    Article  PubMed  CAS  Google Scholar 

  • Palestine AG, Cantrill HL, Luckie AP, Ai E (1994) Intravitreal treatment of CMV retinitis with an antisense oligonucleotide, ISIS 2922, 10th international conference on AIDS and the international conference on STD, Yokohama, Japan, August 1994, vol 2, p 404

    Google Scholar 

  • Palestine AG, Cantrill H, Ai E, Liberman R (1995) Treatment of cytomegalovirus retinitis with ISIS 2922. Invest Ophthalmol Vis Sci 36:S181

    Google Scholar 

  • Plenat F (1996) Animal models of antisense oligonucleotides: lessons for use in humans. Mol Med Today 2:250–257

    Article  PubMed  CAS  Google Scholar 

  • 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 147:124–135

    Google Scholar 

  • Rappaport J, Hanss B, Kopp JB, Copelend TD, Bruggeman LA, Coffman TM, Klotman PE (1995) Transport of phosphorothioate oligonucleotide in kidney: implications for molecular therapy. Kidney Int 47:1462–1469

    Article  PubMed  CAS  Google Scholar 

  • Rapaport E, Levina A, Metelev V, Zamecnik PC (1996) Antimycobacterial activities of antisense oligodeoxynucleotide phosphorothioates in drug-resistant strains. Proc Natl Acad Sci USA 93:709–713

    Article  PubMed  CAS  Google Scholar 

  • Rifai A, Brysch W, Fadden K, Clark J, Schlingensiepen KH (1996) Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice. Am J Pathol 149:717–725

    PubMed  CAS  Google Scholar 

  • Rosenberger RD (1989) Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 87:2S–3S

    Article  Google Scholar 

  • Sadler TW, Liu ET, Augustine KA (1995) Antisense targeting of Engrailed-1 causes abnormal axis formation in mouse embryos. Teratology 51:292–299

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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 45:932–943

    PubMed  CAS  Google Scholar 

  • Sarmiento UM, Perez JR, Becker JM, Narayanan R (1994) In vivo toxicological effects of rel A antisense phosphorothioates in CD-1 mice. Antisense Res Dev 4:99107

    Google Scholar 

  • 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 5:279–287

    PubMed  CAS  Google Scholar 

  • Srinivasan SK, Iversen P (1995a) Review of in vivo pharmacokinetics and toxicology of phosphorothioate oligonucleotides. J Clin Lab Anal 9:129–137

    Article  CAS  Google Scholar 

  • Srinivasan SK, Tewary HK, Iversen PL (1995b) Characterization of binding sites, extent of binding and drug interactions of oligonucleotides with albumin. Antisense Res Dev 5:131–139

    CAS  Google Scholar 

  • Stepkowski SM, Tu Y, Condon TP, Bennett CF (1994a) Blocking of heart allograft rejection by intercellular adhesion molecule-1 antisense oligonucleotides alone or in combination with other immunosuppressive modalities. J Immunol 153:5336–5346

    CAS  Google Scholar 

  • 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 45:1058–1065

    PubMed  CAS  Google Scholar 

  • Temsamani J, Tang J-Y, Padmapriya A, Kubert M, Agrawal S (1993) Pharmacokinetics, biodistribution, and stability of capped oligodeoxynucleotide phosphorothioates in mice. Antisense Res Dev 3:277–284

    PubMed  CAS  Google Scholar 

  • Wallace TL, Bazemore SA, Kornbrust DJ, Cossum PA (1996a) Repeat-dose toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after bolus intravenous administration to cynomolgus monkeys 2. J Pharmacol Exp Ther 278:1313–1317

    CAS  Google Scholar 

  • Wallace TL, Bazemore SA, Kornbrust DJ, Cossum PA (1996b) Single-dose hemodynamic toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after intravenous infusion to cynomolgus monkeys 1. J Pharmacol Exp Ther 278:1306–1312

    CAS  Google Scholar 

  • Wu-Pong S, Weiss TL, Hunt AC (1994) Antisense c-myc oligonucleotide cellular uptake and activity. Antisense Res Dev 4:155–163

    PubMed  CAS  Google Scholar 

  • 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 4:119–122

    PubMed  CAS  Google Scholar 

  • Yi A-K, Chace JH, Cowdery JS, Krieg AM (1996) IFN-gamma promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligonucleotides. Immunology 156:558–564

    CAS  Google Scholar 

  • Zhao Q, Temsamani J, ladarola PL, Jiang Z, Agrawal S (1995) Effect of different chemically modified oligodeoxynucleotides on immune stimulation. Biochem Pharmacol 51:173–182

    Google Scholar 

Download references

Authors
  1. A. A. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. K. Monteith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. M. Leeds
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. L. Nicklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. S. Geary
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. V. Templin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. P. Henry
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. ISIS Pharmaceuticals, Inc., Carlsbad Research Center, 2292 Faraday Avenue, Carlsbad, CA, 92008, USA

    Stanley T. Crooke M.D., Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Levin, A.A. et al. (1998). Toxicity of Oligodeoxynucleotide Therapeutic Agents. In: Crooke, S.T. (eds) Antisense Research and Application. Handbook of Experimental Pharmacology, vol 131. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-58785-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-58785-6_5

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63730-8

  • Online ISBN: 978-3-642-58785-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation