Advertisement

Molekulargenetische Grundlagen in der Tumortherapie

  • M. A. Brach
  • Claudia Sott
  • M. Kiehntopf
  • F. Herrmann
Conference paper

Zusammenfassung

Die normale Zelle unterliegt in ihrem biologischen Verhalten der Kontrolle extrazellulärer Signale. Die Einsicht in die Prinzipien der Signalerkennung und Verarbeitung, in die Regeln der interzellulären Kommunikation und des intrazellulären Zusammenspiels von Proteinen mit Proteinen und DNS wird zusehends erweitert und vertieft. In Einzelfällen ist es möglich, die Schritte der Signaltransduktion. von der Ligandbindung über die Rezeptoraktivierung und Aufschlüsselung der an der Signalübertragung teilhabendenen Moleküle bis hin zur Aktivierung distinkter genetischer Programme im Kern zu verfolgen. Errungen wurde dieser Kenntnisgewinn durch detaillierte biochemische und molekularbiologische Untersuchungen intrazellulärer Vorgänge und nicht zuletzt mit der durch Kristallographie und NMR-Technologie ermöglichten Aufklärung der dreidimensionalen Struktur von Molekülen und ihren Interaktionen. Entscheidende Hinweise für die Aufdeckung von Protein-Funktionen und Protein-Interaktionen kamen zudem aus der molekularbiologischen und biochemischen Charakterisierung genetischer Veränderungen, die Tumorentstehung und Tumorprogression begleiten. Dies hat es erlaubt, nicht nur eine größere Anzahl von (Krebs)genen zu identifizieren, ihre genetische Information zu entschlüsseln und die biologische Funktion ihrer Proteine zu charakterisieren, sondern hat auch unser Verständnis physiologischer Regulationsmechanismen grundlegend erweitert. Die Kenntnis der molekularen Zusammenhänge von Krebsentstehung und Krebsprogression ist eine solide Grundlage für die Entwicklung neuer therapeutischer Interventionsmöglichkeiten, die neben gentherapeutischen Ansätzen auch die Entwicklung neuartiger Wirksubstanzen umfassen.

Summary

Normal cellular behavior is controlled by extracellular signals. Much insights into the mechanisms of ligand binding and signal transduction has been gained in recent years. We beginn to understand intercellular communication and to dissect intracellular protein-protein and protein-DNA interactions. Signals reaching the cell surface are being traced into the nucleus where they activate transcription factors and thereby promote the induction of a specific gene programm. Both biochemical and molecular studies as well as NMR- or christallography-based structural analysis of molecules and their interactions have contributed to the accumulation of the current knowledge. Moreover, molecular and biochemical characterization of genetic alterations known to be involved in the initiation or progression of malignancies have provided substantial clues to our understanding of protein function and protein interaction. This did not only led to the identification and functional characterization of novel oncogenes but also elucidated the principles governing normal cell behavior. Increasing the insight into the molecular genesis of cancer should provide a good basis for elaborating new therapeutic concepts such as both gene therapy and the development of novel compounds to specifically target the tumor cell.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Aaronson SA (1991) Growth factors and cancer. Science 254:1146–1152.PubMedCrossRefGoogle Scholar
  2. 2.
    Bishop JM (1991) Molecular themes in oncology. Cell 64:235–240.PubMedCrossRefGoogle Scholar
  3. 3.
    Boguski MS, McCormick F (1993) Proteins regulating ras and its relatives. Nature 366:643–646.PubMedCrossRefGoogle Scholar
  4. 4.
    Brach MA, Gruss HJ, Sott C, Herrmann F (1993) The mitogenic response to Tumor Necrosis Factor-a requires c-jun/AP-1. Mol Cell Biol 13:4824–4830.Google Scholar
  5. 5.
    Brach MA, Herrmann F (1994) Transcription factors in the mitogenic response to cytokines. In: Mertelsmann R, Herrmann F (eds), Hematopoieitic growth factors in clinical aplication, Dekker, New York, pp 63–83.Google Scholar
  6. 6.
    Caesar G (1993) Oncogenes, antioncogenes, and a hypothesis on cancer therapy, i.e. the origin of cancer, and the prevention of its activity. Med Hypotheses 40:15–18.PubMedCrossRefGoogle Scholar
  7. 7.
    Capecchi MR (1989) Altering the genome by homologous recombination. Science 244:1288–1292.PubMedCrossRefGoogle Scholar
  8. 8.
    Castaigne S, Lefebvre P, Chomienne C, Suc E, Rigal HF, Gardin C, Delmer A, Archimbaud E, Tilly H, Janvier M et al. (1993) Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia. Blood 82:3560–3563.PubMedGoogle Scholar
  9. 9.
    Cleary ML (1991) Oncogenic conversion of transcription factors by chromosomal translocation. Cell 66:619–629.PubMedCrossRefGoogle Scholar
  10. 10.
    Dive C, Evans CA, Whetton AD (1992) Induction of apoptosis-new targets for cancer chemotherapy. Semin Cancer Biol 3:417–427.PubMedGoogle Scholar
  11. 11.
    Eng C, Ponder BA (1993) The role of gene mutations in the genesis of familial cancers. Faseb J 7:910–919.PubMedGoogle Scholar
  12. 12.
    Fantl WJ, Escobedo JA, Martin GA, Turck CW, McCormick F, Williams LT (1992) Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 69:413–423.PubMedCrossRefGoogle Scholar
  13. 13.
    Feinberg AP (1993) Genomic imprinting and gene activation in cancer. Nat Genet 4:110–113.PubMedCrossRefGoogle Scholar
  14. 14.
    Gibbs JB, Oliff A, Kohl NE (1994) Farnesyltransferase Inhibitors: ras research yields a potential cancer therapeutic. Cell 77:175–178.PubMedCrossRefGoogle Scholar
  15. 15.
    Herrmann F, Brach MA, (im Druck) “Anti”-Gentherapie. In: Kompendium der Internistischen Onkologie. Springer, Berlin Heidelberg New York Tokyo.Google Scholar
  16. 16.
    Israel MA (1993) Molecular approaches to cancer therapy. Adv Cancer Res 61:57–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Kastan MB, Zhan O, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ (1992) A mammalian cell cycle checkpoint pathway utilizing p 53 and GADD45 is defective in ataxia-telangiectasia. Cell 71:587–597.PubMedCrossRefGoogle Scholar
  18. 18.
    Kiehntopf M, Brach MA, Licht T, Herrmann F (1995) Ribozyme mediated cleavage of MDR-1 mRNA, a possible approach to reversal multiple durg resistance phenotype in cancer chemotherapy. EMBO J 14:1156.Google Scholar
  19. 19.
    Leach FS, Eledge SJ, Sherr CJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B (1993) Amplification of cyclin genes in colorectal caarcinomas. Canc Res 53:1986–1989.Google Scholar
  20. 20.
    Lowe S, Ruley HE, Jacks T, Housman DE (1993) p 53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–963.PubMedCrossRefGoogle Scholar
  21. 21.
    Lu X, Lane DP (1993) Differential induction of transcriptionally active p 53 following UV or ionizing radiation: Defects in chromosome instability syndromes? Cell 75:765–778.PubMedCrossRefGoogle Scholar
  22. 22.
    Mitchell PJ, Tijan R (1989) Transcriptional regulation on mammalian cells by sequence-specific DNA binding proteins. Science 245:371–378.PubMedCrossRefGoogle Scholar
  23. 23.
    Miyajima A, Kitamura T, Harada N, Yokota T, Arai K (1992) Cytokine receptors and signal transduction. Annu Rev Immunol 10:295–331.PubMedCrossRefGoogle Scholar
  24. 24.
    Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look TA (1994) Fusion of a kinase gene, ALK, to a nuclear protein gene, NPM, in Non-Hodgkin’s lymphoma. Science 263:1281–1284.PubMedCrossRefGoogle Scholar
  25. 25.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756.PubMedCrossRefGoogle Scholar
  26. 26.
    Papadopulus N, Nicolaides NC, Wei Y-E et al. (1994) Mutation of a mutL Homolog in hereditary colon cancer. Science 263:1625–1629.CrossRefGoogle Scholar
  27. 27.
    Raff MC (1992) Social control on cell survival and cell death. Nature 356:397–400.PubMedCrossRefGoogle Scholar
  28. 28.
    Sachs L, Lotem J (1993) Control of programmed cell death in normal and leukemic cells. new implications for therapy. Blood 82:15–21.PubMedGoogle Scholar
  29. 29.
    Sherr C (1994) the ins and outs of RB: coupling gene expression to the cell cycle clock. Trends Cell Biol 4:15–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Tao MH, Levy R (1993) Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as a vaccine for b-cell lymphoma. Nature 362:755–758PubMedCrossRefGoogle Scholar
  31. 31.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite in cancer of the proximal colon. Science 260:816–819.PubMedCrossRefGoogle Scholar
  32. 32.
    Varmus H, Weinberg RA (1993) Genes and the biology of cancer. Freeman, New York.Google Scholar
  33. 33.
    Vaux D1 (1993) Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci USA 90:786–789.PubMedCrossRefGoogle Scholar
  34. 34.
    Vogelstein B, Kinzler K (1992) p 53 Function and Dysfunction. Cell 70:523–525.PubMedCrossRefGoogle Scholar
  35. 35.
    Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141.PubMedCrossRefGoogle Scholar
  36. 36.
    Witte ON (1993) Role of the bcr-abl oncogene in human leukemia. Canc Res 53:485–489.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • M. A. Brach
  • Claudia Sott
  • M. Kiehntopf
  • F. Herrmann

There are no affiliations available

Personalised recommendations