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Biochemical Modulation of Cytotoxic Drugs by Cytokines: Molecular Mechanisms in Experimental Oncology

  • Conference paper
Skin Cancer: Basic Science, Clinical Research and Treatment

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 139))

Abstract

The combination of cytokines and cytotoxic drugs offers a new approach to increase the therapeutic index in the treatment of neoplastic diseases. There is no consensus on optimal strategies for combining these agents so far. The molecular mechanisms underlying the interaction, however, should be defined in order to design clinical trials based on preclinical rationales. The broad spectrum of cytotoxic drugs whose activity can be enhanced by cytokines argues for multiple levels of drug interaction in vitro: alteration in the cellular drug uptake, modulation of drug target enzymes, and changes in metabolism or disposition of a drug. In vivo interaction between cytokines and cytotoxic agents involves an additional layer of complexity because of the effects of cytokines on the host immune system and on drug-metabolizing enzymes. A major mechanism involved in the synergistic interaction of interferon (IFN) and 5-fluorouracil (5-FU) seems to be the increase of active 5-FU metabolites by IFN. Moreover, IFN can reverse resistance against 5-FU by inhibiting the overexpression of thymidylate synthase. The absence of cytokinetic effects of IFN and FU argues against the recruitment of Gs cells into the cell cycle. Topoisomerase has emerged as a critical intracelluar target of cytotoxic drugs. There is convincing evidence that the synergy between tumor necrosis factor (TNF) and topoisomerase-targeted inter-calative (Adriamycin, doxorubicin hydrochloride; m-AMSA, amsacrine; mitoxantrone) and nonintercalative (VM-16, etoposide; VM-26, teniposide) drugs is related to a rapid increase in specific activity of topoisomerase I and II, resulting in enhanced DNA strand breaks and cleavage complex. Furthermore, sensitivity to topoisomerase II targeted drugs can be enhanced by granulocyte colony-stimulating factor (G-CSF) through elevated enzyme activity in tumor cell response to G-CSF. The synergistic interaction between cytokines and cytotoxic agents seems to be sequence dependent. It has recently been demonstrated that newly synthesized metal compounds and IFN are synergistic only after preincubation with cytokines. Cytokines can modulate expression of adhesion receptors on tumor cell lines, thereby influencing their metastatic potential. A considerable number of phase II trials with combination of cytokines and cytotoxic drugs based on these mechanisms have demonstrated promising response rates and tolerable toxicity. Phase III trials are currently in progress to identify enhanced activity combining cytokines and cytotoxic drugs in the treatment of malignancies.

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References

  • 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 47:2403–2406

    PubMed  CAS  Google Scholar 

  • 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 77:700–711

    PubMed  CAS  Google Scholar 

  • 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 2:2810–2814

    Google Scholar 

  • Brach MA, Riedel D, Mertelsmann RH et al (1990) Synergistic effect of rebombinant human leukemia inhibitory factor (LIF) and 1-β-D arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. Leukemia 4:646–649

    PubMed  CAS  Google Scholar 

  • Brach MA, Mertelsmann RH, Herrmann F (1991) Hematopoietins in combination with l-β-D arabinofuranosylcytosine: a possible strategy for improved treatment of myeloid disorders. Semin Oncol 18 [Suppl J]: 16–20

    Google Scholar 

  • 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 3:328–334

    PubMed  CAS  Google Scholar 

  • Chen GL, Yang L, Rowe TC et al (1984) Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259:13560–13566

    PubMed  CAS  Google Scholar 

  • 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: 5834–5840

    PubMed  CAS  Google Scholar 

  • Chu E, Koeller DM, Casey JL et al (1991) Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci USA 88:8977–8981

    Article  PubMed  CAS  Google Scholar 

  • 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 biphenotypic leukemic cell line. Blood 78:94–102

    PubMed  CAS  Google Scholar 

  • 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 50:304–309

    PubMed  Google Scholar 

  • Eifel PJ, Walker SM, Lucas ZJ (1975) Standardization of a sensitive and rapid assay for lymphotoxin. Cell Immunol 15:208–221

    Article  PubMed  CAS  Google Scholar 

  • Elias L, Crissman HA (1988) Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiprolifeartie responses and synergistic interactions with halogenated pyrimidine antimetabolites. Cancer Res 48:4868–4873

    PubMed  CAS  Google Scholar 

  • Foon KA (1989) Biological response modifiers: the new immunotherapy. Cancer Res 49:1621–1639

    PubMed  CAS  Google Scholar 

  • Grem JL, McAtee N, 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 9:1811–1820

    PubMed  CAS  Google Scholar 

  • 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 67:1448–1453

    Google Scholar 

  • Hanna MG, Peters LC, Haspel MV et al (1991) Fundamental and applied aspects of successful active specific immunotherapy of cancer. In: Oldham RK (ed) Principles of cancer biotherapy. Dekker, New York, p 253

    Google Scholar 

  • 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 85:1086–1090

    Article  PubMed  CAS  Google Scholar 

  • Hiddemann W, Kiehl M, Zühlsdorf 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 18 [Suppl J]:21–24

    Google Scholar 

  • 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 18:73–81

    Google Scholar 

  • Kreuser ED, Schröder JK, Kintzel C et al (1994) Cytokine-mediated VLA modulation can influence the adhesion of human colon cancer cells to extracellular matrix proteins. Eicosanoid 4:16

    Google Scholar 

  • Liu LF, Liu CC, Alberts BM (1980) Type II DNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible double-strand break. Cell 19:697–707

    Article  PubMed  CAS  Google Scholar 

  • 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 69:421–423

    PubMed  CAS  Google Scholar 

  • Miyauchi J, Wang C, Kelleher CA et al (1988) The effects of recombinant CSF-1 on the blast cels of acute myeloblastic leukemia in supension culture. J Cell Physiol 135:55–62

    Article  PubMed  CAS  Google Scholar 

  • 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: 1272–1278

    PubMed  CAS  Google Scholar 

  • Nakamura S, Kashimoto S, Kajikawa F et al (1991) Combination effect of recombinant human inerleukin 1 a with antitumor drugs on syngeneic tumors in mice. Cancer Res 51:215–221

    PubMed  CAS  Google Scholar 

  • Oldham RK (1991) Cancer biotherapy: general principles. In: Oldham RK (ed) Principles of cancer biotherapy. Dekker, New York, pp 1–21

    Google Scholar 

  • Ostrove JM, Gifford GE (1979) Stimulation of RNA synthesis in L929 cells by rabbit tumor necrosis factor. Proc Soc Exp Biol Med 160:354–358

    PubMed  CAS  Google Scholar 

  • Pfeffer LM, Tamm I (1984) Interferon inhibition of thymidine incorporation into DNA through effects on thymidine transport and uptake. J Cell Physiol 121: 431–436

    Article  PubMed  CAS  Google Scholar 

  • Rivoltini L, Colombo M, Supino R et al (1990) Modulation of multidrug resistance by verapamil of mdrl1 anti-sense oligodeoxynucleotide does not change the high susceptibility to lymphokine-activated killers in mdr-resistant human carcinoma (LoVo) line. Int J Cancer 46:727–732

    Article  PubMed  CAS  Google Scholar 

  • Teichmann JV, Ludwig WD, Thiel E (1991) Augmentation of the susceptibility of human leukemia to lymphokine-activated killer (LAK) cells by exposure of the leukemic target cells to cytotoxic drugs in vitro and in vivo. Leuk Lymph 5:263–271

    Article  Google Scholar 

  • 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 259:9182–9187

    CAS  Google Scholar 

  • Towatari M, Ito Y, Morishita Y et al (1990) Enhanced expression of DNA topoisomerase II by recombinant human granulocyte colony-stimulating factor in human leukemia cells. Cancer Res 50:7198–7202

    PubMed  CAS  Google Scholar 

  • 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 64:451–465

    PubMed  Google Scholar 

  • Wadler S (1991) The role of immunotherapy in colorectal cancer. Semin Oncol 18 [Suppl J]:27–38

    PubMed  CAS  Google Scholar 

  • Wadler S, Schwartz EL (1990) Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 50:3473–3486

    PubMed  CAS  Google Scholar 

  • Wang JC (1987) Recent studies of DNA topoisomerases. Biochem Biophys Acta 909:1–9

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Klinikum Steglitz, Free University of Berlin, Hindenburgdamn 30, 12200, Berlin, Germany

    E. D. Kreuser

  2. Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA

    S. Wadler & E. Thiel

Authors
  1. E. D. Kreuser
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  2. S. Wadler
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  3. E. Thiel
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Editor information

Editors and Affiliations

  1. University Department of Dermatology Medical Centre Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    Claus Garbe , Stefan Schmitz  & Constantin E. Orfanos ,  & 

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© 1995 Springer-Verlag Berlin · Heidelberg

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Kreuser, E.D., Wadler, S., Thiel, E. (1995). Biochemical Modulation of Cytotoxic Drugs by Cytokines: Molecular Mechanisms in Experimental Oncology. In: Garbe, C., Schmitz, S., Orfanos, C.E. (eds) Skin Cancer: Basic Science, Clinical Research and Treatment. Recent Results in Cancer Research, vol 139. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78771-3_28

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  • DOI: https://doi.org/10.1007/978-3-642-78771-3_28

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-78773-7

  • Online ISBN: 978-3-642-78771-3

  • eBook Packages: Springer Book Archive

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