Skip to main content

Advertisement

SpringerLink
Log in

Krebsbehandlung mit Antisense-Molekülen

Wissenschaftliche Aspekte und klinische Perspektiven

Antisense molecules for targeted cancer therapy

Scientific aspects and clinical perspectives

  • Leitthema
  • Published:
Der Onkologe Aims and scope

Zusammenfassung

Herkömmliche Krebsmedikamente sind unspezifisch wirksam und schädigen auch gesundes Gewebe. Fortschritte im Verständnis der molekularen Besonderheiten von Krebszellen konnten neue Signaltransduktionswege und deren Regulatoren aufzeigen, die spezifisch am malignen Prozess beteiligt und damit für die Entwicklung neuer Krebsmedikamente von Interesse sind. Antisense-Moleküle, einschließlich herkömmlicher Einzelstrang-Antisense-Oligonukleotide (ASO) und kurzer Interferenz-RNA (siRNA), hemmen die Genexpression v. a. auf der Transkriptionsebene. Sie richten sich spezifisch gegen die genetische Ursache von Krebs und lassen sich besonders gut gegen Onkogene einsetzen, deren Proteine für kleinmolekulare Substanzen wie Proteinkinasehemmer oder für therapeutische Antikörper nicht zugänglich sind. Trotz bisher mäßiger Erfolge in klinischen Studien besteht nach wie vor große Hoffnung, dass ASO und siRNA dank der Identifizierung neuer krebsrelevanter Zielstrukturen und Fortschritte in der Nukleinsäureentwicklung die Krebsbehandlung entscheidend verbessern werden.

Abstract

The efficacy of traditional anti-cancer agents is hampered by toxicity to normal tissues. Recent advances in molecular oncology research have led to the identification of signaling pathways and their regulators implicated in tumor development and progression. Consequently, novel biological agents were designed which specifically target key regulators of the malignant process and are superior to unspecific cytotoxic agents. Antisense molecules comprising conventional single-stranded oligonucleotides (ASO) and small interfering RNA (siRNA) inhibit gene expression mainly on the transcript level. Thus, they specifically target the genetic basis of cancer and are particularly useful for inhibiting the expression of oncogenes the protein products of which are inaccessible to small molecules or inhibitory antibodies. Although antisense oncology trials could not fulfill all expectations so far, recent progress in gene expression profiling and nucleic acid development have raised new hopes that this fascinating gene targeting concept will eventually translate into enhanced clinical efficacy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1

Literatur

  1. Allen TM, Cullis PR (2004) Drug delivery systems: entering the mainstream. Science 303: 1818

    Article  PubMed  Google Scholar 

  2. Bernstein E, Caudy AA, Hammond SM et al. (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409: 363

    Article  PubMed  Google Scholar 

  3. Chi KN, Eisenhauer E, Fazli L et al. (2005) A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2’-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 97: 1287

    PubMed  Google Scholar 

  4. Couzin J (2002) Breakthrough of the year. Small RNAs make big splash. Science 298: 2296

    Article  PubMed  Google Scholar 

  5. Gautschi O, Tschopp S, Olie RA et al. (2001) Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins. J Natl Cancer Inst 93: 463

    Article  PubMed  Google Scholar 

  6. Jackson AL, Bartz SR, Schelter J et al. (2003) Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 21: 635

    Article  PubMed  Google Scholar 

  7. Karagiannis TC, El-Osta A (2005) RNA interference and potential therapeutic applications of short interfering RNAs. Cancer Gene Ther 12: 787–795

    Article  PubMed  Google Scholar 

  8. Kirkwood JM, Bedikian AY, Millward MJ et al. (2005) Long-term survival results of a randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM). Proc Am Soc Clin Oncol 24: 7506

    Google Scholar 

  9. Lynch TJ Jr, Raju R, Lind M et al. (2003) Randomized phase III trial of chemotherapy and antisense oligonucleotide LY900003 (ISIS 3521) in patients with advanced NSCLC: initial report. Proc Am Soc Clin Oncol 22: 623

    Google Scholar 

  10. Martinez J, Tuschl T (2004) RISC is a 5‘ phosphomonoester-producing RNA endonuclease. Genes Dev 18: 975

    Article  PubMed  Google Scholar 

  11. Mello CC, Conte D Jr (2004) Revealing the world of RNA interference. Nature 431: 338

    Article  PubMed  Google Scholar 

  12. Millward MJ, Bedikian AY, Conry M et al. (2004) Randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM): Analysis of long-term survival. J Clin Oncol 22: 7505

    Google Scholar 

  13. Monia BP, Lesnik EA, Gonzalez C et al. (1993) Evaluation of 2’-modified oligonucleotides containing 2’-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 268: 14514–14522

    PubMed  Google Scholar 

  14. Morizono K, Chen IS (2005) Targeted Gene Delivery by Intravenous Injection of Retroviral Vectors. Cell Cycle 4

  15. Napoli C, Lemieux C, Jorgensen R (1990) Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans. Plant Cell 2: 279

    Article  PubMed  Google Scholar 

  16. Nielsen PE (2000) Antisense properties of peptide nucleic acid. Methods Enzymol 313: 156

    PubMed  Google Scholar 

  17. Opalinska JB, Gewirtz AM (2002) Nucleic-acid therapeutics: basic principles and recent applications. Nat Rev Drug Discov 1: 503

    Article  PubMed  Google Scholar 

  18. Orum H, Wengel J (2001) Locked nucleic acids: a promising molecular family for gene-function analysis and antisense drug development. Curr Opin Mol Ther 3: 239

    PubMed  Google Scholar 

  19. Raffo A, Lai JC, Stein CA et al. (2004) Antisense RNA down-regulation of bcl-2 expression in DU145 prostate cancer cells does not diminish the cytostatic effects of G3139 (Oblimersen). Clin Cancer Res 10: 3195–3206

    Article  PubMed  Google Scholar 

  20. Sanjuan MA, Rao N, Lai KT et al. (2006) CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion. J Cell Biol 172: 1057–1068

    Article  PubMed  Google Scholar 

  21. Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 23: 709

    Article  PubMed  Google Scholar 

  22. Soutschek J, Akinc A, Bramlage B et al. (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432: 173

    Article  PubMed  Google Scholar 

  23. Stein D, Foster E, Huang SB et al. (1997) A specificity comparison of four antisense types: morpholino, 2’-O-methyl RNA, DNA, and phosphorothioate DNA. Antisense Nucleic Acid Drug Dev 7: 151

    PubMed  Google Scholar 

  24. Stephenson ML, Zamecnik PC (1978) Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci USA 75: 285

    Article  PubMed  Google Scholar 

  25. Tong AW, Zhang YA, Nemunaitis J (2005) Small interfering RNA for experimental cancer therapy. Curr Opin Mol Ther 7: 114

    PubMed  Google Scholar 

  26. Wagner E, Cotten M, Foisner R et al. (1991) Transferrin-polycation-DNA complexes: the effect of polycations on the structure of the complex and DNA delivery to cells. Proc Natl Acad Sci USA 88: 4255

    PubMed  Google Scholar 

  27. Zimmermann TS, Lee AC, Akinc A et al. (2006) RNAi-mediated gene silencing in non-human primates. Nature 441: 111–114

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Es besteht kein Interessenkonflikt. Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.

Author information

Authors and Affiliations

  1. Institut für Pharmakologie, Universität Bern, Friedbühlstraße 49, 3010, Bern, Schweiz

    U. Zangemeister-Wittke

Authors
  1. U. Zangemeister-Wittke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to U. Zangemeister-Wittke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zangemeister-Wittke, U. Krebsbehandlung mit Antisense-Molekülen. Onkologe 13, 256–262 (2007). https://doi.org/10.1007/s00761-006-1170-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00761-006-1170-z

Schlüsselwörter

Keywords

Search

Navigation