Skip to main content
SpringerLink
Log in

Antitumor effects of liposomal IL1α and TNFα against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Interleukin 1 alpha (IL1α) and tumor necrosis factor alpha (TNFα) have been successfully incorporated into specific phosphatidylcholine (PC) and phosphatidylserine (PS) multilamellar vesicle (MLV) liposomes by modifying the concentration of calcium ion and pH of the encapsulation buffer. Under these conditions, some of the cytokines may attach to the exterior surface of the MLV and therefore be readily accessible to target cells for receptor binding and signal transduction. These cytokine-associated liposomes are stable for up to 2 weeks in serum-free buffer, and leakage of cytokines into medium containing 10% fetal bovine serum was about 50% at the end of a 3-day incubation period at 37°C. The biological activities mediated by liposomal IL1α and TNFα were specific: the stimulation of thymidine uptake in T-helper D10 lymphocytes and the cytolysis of TNFα-sensitive L929 target cells could be blocked by specific neutralizing antibodies in a dose-dependent fashion. When administered intravenously into C57BL/6 mice bearing the syngeneic B16F10 murine melanoma cells, dual entrapment of liposomal IL1α and TNFα significantly reduced the number of metastatic tumor nodules in the lungs and prolonged the life span of the animals. Thus, liposomal IL1α and TNFα displayed significant in vivo antitumor activity against the IL1α- and TNFα-resistant B16F10 metastatic murine melanoma.

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

Similar content being viewed by others

References

  1. Nathan, CF, Silverstein, SC, Brukner, LH and Cohn, ZA, 1979, Extracellular cytolysis by activated macrophages and granulocytes II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med, 149, 100–13.

    Google Scholar 

  2. Adams, DO, Kao, K-J, Farb, R and Pizzo, SV, 1980, Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral protease. J Immunol, 124, 293–300.

    Google Scholar 

  3. Reidarson, TH, Granger, GA and Klostergaard, J, 1982, Inducible macrophage cytotoxins. II. Tumor lysis mechanism involving target cell-binding proteases. JNCI, 69, 889–94.

    Google Scholar 

  4. Sone, S, Lopez-Berenstein, G and Fidler, IJ, 1985, Kinetics and function of tumor cytotoxic factor produced by human blood monocytes activated to the tumoricidal state. JNCI, 74, 583–90.

    Google Scholar 

  5. Ferluga, J, Schorlemmer, HU, Baptista, LC and Allison, AC, 1978, Production of the complement cleavage product, C3a, by activated macrophages and its tumorolytic effects. Clin Exp Immunol, 31, 512–17.

    Google Scholar 

  6. Zeigler-Heitbrock, HW, Moller, A, Linke, RP et al., 1986, Tumor necrosis factor as effector molecule in monocytemediated cytotoxicity. Cancer Res, 46, 5947–52.

    Google Scholar 

  7. Philip, R and Epstien, B, 1986, Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, γ-interferon and interleukin-1. Nature, 323, 86–89.

    Google Scholar 

  8. Feinman, R, Henriksen-Destefano, D, Tsujimoto, M and Vilcek, J, 1987, Tumor necrosis factor is an important mediator of tumor killing by human monocytes. J Immunol, 138, 635–40.

    Google Scholar 

  9. Ichinose, Y, Bakouche, O, Tsao, JY and Fidler, IJ, 1988, Tumor necrosis factor and IL-1 associated with plasma membranes of activated human monocytes lyse monokine-sensitive but not monokine-resistant tumor cells whereas viable activated monocytes lyse both. J Immunol, 141, 512–18.

    Google Scholar 

  10. Lovett, D, Kozan, B, Hadam, M, Resch, K and Gemsa, D, 1986, Macrophage cytotoxicity: Interleukin 1 as a mediator of tumor cytostasis. J Immunol, 136, 340–7.

    Google Scholar 

  11. Onozaki, K, Matsushima, K, Kleinerman, ES, Saito, T and Oppenheim, JJ, 1985, Role of interleukin 1 in promoting human monocyte-mediated tumor cytotoxicity. J Immunol, 135, 314–20.

    Google Scholar 

  12. Lachman, LB, Dinarello, CA, Llansa, ND and Fidler, IJ, 1986, Natural and recombinant human interleukin 1-β is cytotoxic for human melanoma cells. J Immunol, 136, 3098–102.

    Google Scholar 

  13. Onozaki, K, Matsushima, K, Aggarwal, BB and Oppenheim, JJ, 1985, Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol, 135, 3962–8.

    Google Scholar 

  14. Fan, D, Price, J, Schackert, H et al., 1989, Antiproliferative activity of liposome-encapsulated transforming growth factor-beta against MDA-MB-435 human breast carcinoma cells. Cancer Commun, 1, 337–43.

    Google Scholar 

  15. Fan, D, Bucana, CD, O'Brian, CA et al., 1990, Enhancement of murine tumor cell sensitivity to adriamycin by presentation of the drug in phosphatidylcholine-phosphatidylserine liposomes. Cancer Res, 50, 3619–26.

    Google Scholar 

  16. Seid, CA, Fidler, IJ, Clyne, RK et al., 1991, Overcoming murine tumor cell resistance to vinblastine by presentation of the drug in multilamellar liposomes consisting of phosphatidylcholine and phosphatidylserine. Selective Cancer Ther, 7, 103–12.

    Google Scholar 

  17. Kaye, SB, Boden, JA and Ryman, BE, 1981, The effect of liposome (phospholipid vesicle) entrapment of actinomycin D and methotrexate on the in vivo treatment of sensitive and resistant solid murine tumours. Eur J Cancer, 17, 279–89.

    Google Scholar 

  18. Mace, K, Mayhew, E, Mihich, E and Ehrke, MJ, 1988, Alteration in murine host defense functions by adriamycin or liposome-encapsulated adriamycin. Cancer Res, 48, 130–6.

    Google Scholar 

  19. Lopez-Berestein, G, Fainstein, V, Hopfer, R, et al., 1985, Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer, a preliminary study. J Infect Dis Adv, 151, 704–10.

    Google Scholar 

  20. Murray, JL, Kleinerman, ES, Cunningham, JE, et al., 1989, Phase I trial of liposomal muramyl-tripeptide-phosphatidylethanolamine in cancer patients. J Clin Oncol, 7, 1915–25.

    Google Scholar 

  21. Fidler, IJ, 1988, Targeting of immunomodulators to mononuclear phagocytes for therapy of cancer. Adv Drug Deliv Rev, 3, 405–18.

    Google Scholar 

  22. Ostro, MJ, 1988, Liposomes. Sci Am, 256, 102–11.

    Google Scholar 

  23. Nii, A, Fan, D and Fidler, IJ, 1991, Cytotoxic potential of liposomes containing tumor necrosis factor-α against sensitive and resistant target cells. J Biol Resp Modifiers, 10, 13–19.

    Google Scholar 

  24. Hume, DA and Nayar, R, 1989, Encapsulation is not involved in the activities of recombinant gamma interferon associated with multilamellar phospholipid liposomes on murine bone marrow-derived macrophages. Lymphokine Res, 8, 415–25.

    Google Scholar 

  25. Bakouche, O, Lachman, LB, Knowles, RD and Kleinerman, ES, 1988, Cytotoxic liposomes: membrane interleukin 1 presented in multilamellar vesicles. Lymphokine Res, 7, 445–56.

    Google Scholar 

  26. Bakoucke, O, Brown, DC and Lachman, LB, 1987, Liposomes expressing IL1 biological activity. J Immunol, 138, 4256–62.

    Google Scholar 

  27. Maeda, M, Knowles, RD and Kleinerman, ES, 1991, Muramyl tripeptide phosphatidylethanolamine encapsulated in liposomes stimulates monocyte production of tumor necrosis factor and interleukin-1 in vitro. Cancer Commun, 3, 313–21.

    Google Scholar 

  28. Fidler, IJ and Schroit, AJ, 1984, Synergism between lymphokines and muramyl dipeptide encapsulated in liposomes: in situ activation of macrophages and therapy of spontaneous cancer metastasis. J Immunol, 133, 515–8.

    Google Scholar 

  29. Nayar, R, Morikawa, K and Fidler, IJ, 1987, Characterization of liposomes containing the chemotactic peptide N-formyl-methionyl-phenylalanine (FMLP) and their interaction with mouse macrophages. Cancer Drug Deliv, 4, 233–44.

    Google Scholar 

  30. Carswell, EA, Green, S, Everson, TC et al., 1975, Effect of tumor necrosis factor on cultured human melanoma cells. Nature, 258, 731–2.

    Google Scholar 

  31. Haranaka, K and Satomi, N, 1981, Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro. Jpn J Exp Med, 51, 191–4.

    Google Scholar 

  32. Dempsey, RA, Dinarello, CA, Mier, JW, et al., 1982, The differential effects of human leukocytic pyrogen/lymphocytic activating factor, T-cell growth factor and interferon on human natural killer cell activity. J Immunol, 129, 2504–10.

    Google Scholar 

  33. Okubo, A, Sone, S, Tanaka, M and Ogura, T, 1989, Membrane-associated interleukin 1α as a mediator of tumor cell killing by human blood monocytes fixed with paraformaldehyde. Cancer Res, 49, 265–70.

    Google Scholar 

  34. Kovacs, EJ, Beckner, SK, Longo, DL et al., 1989, Cytokine gene expression during generation of human lymphokine-activated killer cells: early induction of interleukin-1 beta by interleukin-2. Cancer Res, 49, 940–4.

    Google Scholar 

  35. Kaye, J, Gillis, S, Mizel, SB, et al., 1984, Growth of a cloned helper T-cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin-1 is required for expression of receptors for interleukin-2. J Immunol, 133, 1339–45.

    Google Scholar 

  36. Navarro, S, Debili, N, Bernaudin, J-F, Vainchenker, W and Doty, J, 1989, Regulation of the expression of IL6 in human monocytes. J Immunol, 142, 4339–45.

    Google Scholar 

  37. Kishimoto, T, 1989, The biology of interleukin-6. Blood, 74, 1–10.

    Google Scholar 

  38. Billiau, A, Van Damme, J, Opdenakker, G et al., 1986, Interleukin-1 as a cytokine inducer. Immunobiology, 172, 323–35.

    Google Scholar 

  39. Ostensen, ME, Thiele, DL and Lipsky, PE, 1987, Tumor necrosis factor-alpha enhances cytolytic activity of human natural killer cells. J Immunol, 138, 4185–91.

    Google Scholar 

  40. Carswell, EA, Old, LJ, Kassel, RL et al., 1975, An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA, 72, 3666–70.

    Google Scholar 

  41. Ohnishi, S and Ito, T, 1973, Clustering of lecithin molecules in phosphatidylserine membranes induced by calcium ion binding to phosphatidylserine. Biochem Biophys Res Commun, 51, 132–8.

    Google Scholar 

  42. Papahadjopoulos, D, Vail, WJ, Jacobson, K and Poste, G, 1975, Cochleate lipid cylinders: formation by fusion of unilamellar lipid vesicles. Biochem Biophys Acta, 394, 483–91.

    Google Scholar 

  43. Hope, MJ and Cullis, PR, 1980, Effect of divalent cations and pH on phosphatidylserine model membranes: a 31P NMR study. Biochem Biophys Res Commun, 92, 846–52.

    Google Scholar 

  44. Chiruvolu, S, Walker, S, Israelachvili, J et al., 1994, Higher order self-assembly of vesicles by site-specific binding. Science, 264, 1753–6.

    Google Scholar 

  45. Creutz, CE, 1992, The annexins and exocytosis. Science, 258, 924–31.

    Google Scholar 

  46. Drust, DS and Creutz, CE, 1988, Aggregation of chromaffin in granules by calpactin at micromolar levels of calcium. Nature, 331, 88–91.

    Google Scholar 

  47. Dinarello, CA, 1992, Role of interleukin-1 in infectious diseases. Immunol Rev, 127, 119–46.

    Google Scholar 

  48. Fidler, IJ, Nii, A, Tsao, JY, Davis, S and Kleinerman, ES, 1989, Activated human blood monocytes trigger the antitumor activity of blood polymorphonuclear cells. Lymphokine Res, 8, 427–37.

    Google Scholar 

  49. Anderson, PM, Hanson, DC, Hasz, DE et al., 1994, Cytokines in liposomes: preliminary studies with IL-1, IL-2, IL-6, GM-CSF and interferon-gamma. Cytokine, 6, 92–101.

    Google Scholar 

  50. Pezzella, KM, Neville, E and Huang, JJ, 1990, In vivo inhibition of tumor growth of B16 melanoma by recombinant interleukin Iβ. I. Tumor inhibition parallels lymphocyte-activating factor activity of interleukin 1β protein. Cytokine, 2, 357–62.

    Google Scholar 

  51. Neville, ME, Pezzella, KM, Schmidt, K, Galbraith, W and Ackerman, N, 1990, In vivo inhibition of tumor growth of B16 melanoma by recombinant interleukin 1β. II. Mechanism of inhibition: the role of polymorphonuclear leukocytes. Cytokine, 2, 456–63.

    Google Scholar 

  52. Ichinose, Y, Tsao, JY and Fidler, IJ, 1988, Destruction of tumor cells by monokines released from activated human blood monocytes: evidence for parallel and additive effects of IL-1 and TNF. Cancer Immunol Immunother, 27, 7–12.

    Google Scholar 

  53. Le, J, Weinstein, D, Gubler, U and Vilcek, J, 1987, Induction of membrane-associated interleukin-1 by tumor necrosis factor in human fibroblasts. J Immunol, 138, 2137–42.

    Google Scholar 

  54. Giavazzi, R, Garofalo, A, Bani, MR, et al., 1990, Interleukin 1-induced augmentation of experimental metastasis from a human melanoma in nude mice. Cancer Res, 50, 4771–5.

    Google Scholar 

  55. Bani, MR, Garofalo, A, Scanziani, E and Giavazzi, R, 1991, Effect of interleukin-1-beta on metastasis formation in different tumor systems. JNCI, 83, 119–23.

    Google Scholar 

  56. Dustin, ML and Springer, TA, 1988, Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol, 107, 321–31.

    Google Scholar 

  57. Dejana, E, Bertocchi, F, Bortolami, MC et al., 1988, Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest, 82, 1466–70.

    Google Scholar 

  58. Lauri, D, Bertomeu, MC, Orr, FW et al., 1990, Interleukin-1 increases tumor cell adhesion to endothelial cells through an RGD dependent mechanism: in vitro and in vivo studies. Clin Exp Metastasis, 8, 27–32.

    Google Scholar 

Download references

Author information

Author notes

  1. Mitsue Saito

    Present address: The 3rd Department of Surgery, Faculty of Medicine, University of Tokyo, 3-28-6 Mejirodai, Bunkyo-ku, 112, Tokyo, Japan

Authors and Affiliations

  1. Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Mitsue Saito, Dominic Fan & Lawrence B. Lachman

Authors
  1. Mitsue Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominic Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lawrence B. Lachman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saito, M., Fan, D. & Lachman, L.B. Antitumor effects of liposomal IL1α and TNFα against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice. Clin Exp Metast 13, 249–259 (1995). https://doi.org/10.1007/BF00133480

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00133480

Keywords

Search

Navigation