Advertisement

Grundlagen der immunologischen und biochemischen Modulation von Zytostatika

  • E. D. Kreuser
  • S. Wadler
  • E. Thiel
Conference paper

Zusammenfassung

Die Kombination von Zytokinen und Zytostatika stellt einen neuen Ansatz in der Behandlung maligner Erkrankungen mit dem Ziel dar, den therapeutischen Index zu erhöhen. Gesicherte Konzepte für eine optimale Kombination dieser Substanzgruppen existieren bislang nicht. Deshalb sollten die molekularen Interaktionsmechanismen zwischen Zytokinen und Zytostatika bekannt sein, damit klinische Studien rational konzipiert werden können. Da die Wirkung von Zytostatika durch verschiedene Zytokine verstärkt werden kann, scheinen die Interaktionen auf verschiedenen Ebenen zu erfolgen: Änderung der Zytostatikaaufnahme in die Zelle, Änderung der Aktivität von Targetenzymen des Zytostatikametabolismus und Beeinflussung der Pharmakokinetik von Zytostatika durch Zytokine. Die Analyse der Interaktionen zwischen Zytokinen und Zytostatika wird darüber hinaus durch die immunmodulatorischen und proliferationsmodulierenden Effekte von Zytokinen erschwert. Ein Mechanismus der synergistischen Interaktion zwischen Interferon (IFN) und 5-Fluorouracil (5-FU) scheint auf einer Erhöhung aktiver Metabolite von 5-FU zu beruhen. Darüber hinaus kann IFN die Entwicklung einer Resistenz gegen 5-FU dadurch verhindern, daß eine Überexpression der Thymidylat-Synthetase blockiert wird. Das Fehlen zytokinetischer Effekte von IFN und 5-FU spricht gegen ein Recruitment von Zellen aus der Go-Phase in den Zellzyklus.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Alexander RB, Nelson WG, Coffey DS (1987) Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. Cancer Res 47: 2403–2406PubMedGoogle Scholar
  2. Bettelheim P, Valent P, Andreeff M et al. (1991) Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia. Blood 77: 700–711PubMedGoogle Scholar
  3. Bhalla K, Birkhofer M, Arlin Z et al. (1988) Effect of recombinant GM-CSF on the metabolism of cytosine-arabinoside in normal and leukemic human bone marrow cells. Leukemia 2810–2814Google Scholar
  4. Brach MA, Riedel D, Mertelsmann RH et al. (1990) Synergistic effect of recombinant human leukemia inhibitory factor (LIF) and 1-ß-D arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. Leukemia: 4: 646–649PubMedGoogle Scholar
  5. Brach MA, Mertelsmann RH, Herrmann F (1991) Hematopoietins in combination with 1-ß-D arabinofuranosylcytosine: a possible strategy for improved treatment of myeloid disorders. Semin Oncol 18 (Suppl J): 16–20Google Scholar
  6. Cannistra SA, Groshek P, Griffin JD (1989) Granulocyte-macrophage colony stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia. Leukemia 3:328–334PubMedGoogle Scholar
  7. Chen GL,Yang L, RoweTCet al. (1984) Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259: 13560–13566PubMedGoogle Scholar
  8. Chu E, Zinn S, Boarman D et al. (1990) The interactions of gamma interferon and 5-fluorouracil in the H630 human colon carcinoma cell line. Cancer Res 50: 5834–5840PubMedGoogle Scholar
  9. Cohen A, Grunberger T,Vanek W et al. (1991) Constitutive expression and role in growth regulation of interleukin-1 and multiple cytokine receptors in a biophenotypic leukemic cell line. Blood 78: 94–102PubMedGoogle Scholar
  10. De Jong S, Zijlstra JG, de Vries EGE et al. (1990) Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin resistant human small cell lung carcinoma cell line. Cancer Res 50: 304–309PubMedGoogle Scholar
  11. Eifel PJ, Walker SM, Lucas ZJ (1975) Standardization of a sensitive and rapid assay for lymphotoxin. Cell Immunol: 15: 208–221PubMedCrossRefGoogle Scholar
  12. Elias L, Crissman HA (1988) Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidi- ne antimetabolites. Cancer Res 48: 4868–4873PubMedGoogle Scholar
  13. Foon KA (1989) Biological response modifiers: the new immunotherapy. Cancer Res 49: 1621–1639PubMedGoogle Scholar
  14. Grem JL, McAtee NM, Murphy RF et al. (1991) A pilot study of interferon α-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol 9: 1811–1820PubMedGoogle Scholar
  15. Griffin JD, Herrmann YF, Wiper D et al. (1989) Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia. Blood 67: 1448–1453Google Scholar
  16. Hanna MG, Peters C, Haspel MV et al. (1991) Fundamental and applied aspects of successful active specific immunotherapy of cancer. In: Oldham RG (ed) Principles of cancer biotherapy. Dekker, New York, p 253Google Scholar
  17. Heck MMS, Hittelman WN, Earnshaw WC (1988) Differential expression of DNA topoisomerase I and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 85:1086–1090PubMedCrossRefGoogle Scholar
  18. Hiddemann W, Kiehl M, Zuhlsdorf M et al. (1991) Granulocyte-Macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia. Semin Oncol 19 [Suppl 4]: 31–37Google Scholar
  19. Kreuser ED, Keppler BK, Berdel WE et al. (1991) Synergistic antitumor interactions between newly synthesized ruthenium complexes and cytokines in human colon carcinoma cell lines. Semin Oncol 19 [Suppl 3]: 73–81Google Scholar
  20. Liu LF, Liu CC, Alberts BM (1980) Type ITDNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible doublestrand break. Cell 19: 697–707PubMedCrossRefGoogle Scholar
  21. Martin DS, Stolfi RL, Sawyer RC et al. (1985) Application of biochemical modulation with a therapeutically inactive modulating agent in clinical trials of cancer chemotherapy. Cancer Treat Rep 69: 421–423PubMedGoogle Scholar
  22. Miyauchi J,Wang C, Kelleher CA et al. (1988) The effects of recombinant CSF-1 on the blast cells of acute myeloblastic leukemia in supension culture. J Cell Physiol 135:55–62PubMedCrossRefGoogle Scholar
  23. Miyauchi J, Kelleher CA, Wang C et al. (1989) Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 73: 1272–1278PubMedGoogle Scholar
  24. Nakamura S, Kashimoto S, Kajikawa F et al. (1991) Combination effect of recombinant human interleukin 1 a with antitumor drugs on syngeneic tumors in mice. Cancer Res 51: 215–221PubMedGoogle Scholar
  25. Oldham RK (1991) Cancer biotherapy: general principles. In: Qldham RG (ed) Principles of cancer biotherapy. Dekker, New York, pp 1–21Google Scholar
  26. Ostrove JM, Gifford GE (1979) Stimulation of RNA synthesis in L929 cells by rabbit tumor necrosis factor. Proc Soc Exp Biol Med 160: 354–358PubMedGoogle Scholar
  27. Pfeffer M, Tamm I (1984) Interferon inhibition of thymidine incorporation into DNA through effects on thymidine transport and uptake. J Cell Physiol 121: 431–436PubMedCrossRefGoogle Scholar
  28. Rivoltini L, Colombo M, Supino R et al. (1990) Modulation of multidrug resistance by verapamil of mdr1 anti-sense oligodeoxynucleotide does not change the high susceptibility to lymphokine-activated killers in mdr-resistant human carcinoma (LoVo) line. Int J Cancer 46: 727–732PubMedCrossRefGoogle Scholar
  29. Teichmann JV, Ludwig WD, Thiel E (1991) Augmentation of susceptibility of human leukemia to lymphokine-activated killer (LAK) cells by exposure of the leukemic target cells to cytotoxic drugs in vitro und in vivo. Leukemia Lymphoma 5: 263–271CrossRefGoogle Scholar
  30. Tewey KM, Chen GL, Nelson EM et al. (1984) Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259: 9182–9187PubMedGoogle Scholar
  31. Towatari M, ItoY, MorishitaYet al. (1990) Enhanced expression of DNA topoisomerase II by recombinant human granulocyte colony-stimulating factor in human leukemia cells. Cancer Res 50: 7198 – 2702PubMedGoogle Scholar
  32. Van Haelst-Pisani CM, Pisani RJ, Kovach JS (1989) Cancer immunotherapy: current status of treatment with interleukin 2 and lymphokine-activated killer cells. Mayo Clin Proc 64: 451–465PubMedGoogle Scholar
  33. Wadler S (1991) The role of immunotherapy in colorectal cancer. Semin Oncol 18 (Suppl J):27–38PubMedGoogle Scholar
  34. Wadler S, Schwartz EL (1990) Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 50: 3473 – 3486PubMedGoogle Scholar
  35. Wang JC (1987) Recent studies of DNA topoisomerases. Biochem Biophys Acta 909:1–9PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • E. D. Kreuser
    • 1
  • S. Wadler
    • 2
  • E. Thiel
    • 1
  1. 1.Abteilung Innere Medizin mit Schwerpunkt Hämatologie und Onkologie, Universitätsklinikum SteglitzFreie UniversitätBerlinDeutschland
  2. 2.Department of Qncology, Albert Einstein College of MedicineMontefiore Medical CenterBronxUSA

Personalised recommendations