Skip to main content
Log in

Comparative efficacy of liposomes containing synthetic bacterial cell wall analogues for tumoricidal activation of monocytes and macrophages

  • Original articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

We examined the activation to the tumoricidal state of normal mouse peritoneal exudate macrophages, bone marrow macrophages, and human blood monocytes by liposomes containing either lipophilic muramyl tripeptide (CGP 19 835) or a new synthetic analogue of lipoprotein from gram-negative bacteria outer wall, CGP 31 362, or combinations of the two. The superiority of liposomes containing the synthetic lipopeptide over liposomes containing lipophilic muramyl tripeptide for in vitro activation of monocytes and macrophages was demonstrated in several experiments. First, liposome-CGP-19 835 activated monocytes only in the presence of interferon-γ, whereas activation with liposome-CGP 31 362 was interferon-independent. Second, activation of both mouse macrophages and human blood monocytes by liposome-CGP 31 362 occurred at a lower liposomal concentration than that by liposome-CGP 19 835. Third, monocytes incubated with liposome-CGP 31 362 released both tumor necrosis factor (TNF) and interleukin-1 activities, whereas monocytes treated with liposome-CGP 19 835 (in the absence of interferon-γ) released only TNF activity. These data suggest that liposomes containing the synthetic lipopeptide CGP 31 362 are superior to liposomes containing CGP 19 835 for systemic activation of macrophages.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Adams DO, Marino PA (1981) Evidence for a multistep mechanism of cytolysis by BCG-activated macrophages: the interrelationship between the capacity for cytolysis, target binding, and secretion of cytolytic factor. J Immunol 126: 981

    Google Scholar 

  2. Adams DO, Kao K-J, Farb R, Pizzo SV (1980) Effector mechanisms of cytolytically activated macrophages: II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neural proteases. J Immunol 124: 293

    Google Scholar 

  3. Alving CR (1983) Delivery of liposome-encapsulated drugs to macrophages. Pharmacol Ther 22: 407

    Google Scholar 

  4. Brodt P, Blore J, Phillips NC, Munzer JS, Rioux JD (1989) Inhibition of murine hepatic tumor growth by liposomes containing a lipophilic muramyl dipeptide. Cancer Immunol Immunother 28: 54

    Google Scholar 

  5. Currie GA, Basham C (1978) Differential arginine dependence and the selective cytotoxic effects of activated macrophages for malignant cells in vitro. Br J Cancer 38: 653

    Google Scholar 

  6. Daous SS, Hume LR, Juliano R (1989) Liposomes in cancer therapy. Adv Drug Delivery Rev 3: 405

    Google Scholar 

  7. Decker T, Lohmann-Mathes ML, Gifford GE (1987) Cell-associated tumor necrosis factor (TNF) as a killing mechanism of activated cytotoxic macrophages. J Immunol 138: 957

    Google Scholar 

  8. Ferluga J, Schorlemmer HU, Baptista LC, Allison AC (1978) Production of the complement cleavage product, C3a, by activated macrophages and its tumorilytic effects. Clin Exp Immunol 31: 512

    Google Scholar 

  9. Fidler IJ (1981) The in situ induction of tumoricidal activity in alveolar macrophages by liposomes containing muramyl dipeptide is a thymus-independent process. J Immunol 127: 1719

    Google Scholar 

  10. Fidler IJ (1985) Macrophages and metastasis: a biological approach to cancer therapy. Cancer Res 45: 4714

    Google Scholar 

  11. Fidler IJ (1986) Immunomodulation of macrophages for cancer and antiviral therapy. In: Tomlinson E, Davis SS (eds) Site-specific drug delivery. Wiley, New York, p 111

    Google Scholar 

  12. Fidler IJ (1988) Targeting of immunomodulators to mononuclear phagocytes for therapy of cancer. Adv Drug Delivery Rev 2: 69

    Google Scholar 

  13. Fidler IJ, Raz A, Fogler WE, Kirsh R, Bugelski P, Poste G (1980) The design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages. Cancer Res 40: 4460

    Google Scholar 

  14. Fidler IJ, Sone S, Fogler WE, Barnes ZL (1981) Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78: 1680

    Google Scholar 

  15. Fidler IJ, Sone S, Fogler WE, Smith D, Braun DG, Tarcsay L, Gisler RJ, Schroit AJ (1982) Efficacy of liposomes containing a lipophilic muramyl dipeptide for activating the tumoricidal properties of alveolar macrophages in vivo. J Biol Response Modif 1: 43

    Google Scholar 

  16. Fidler IJ, Fogler WE, Tarcsay L, Schumann G, Braun DG, Schroit AJ (1983) Systemic activation of macrophages and treatment of cancer metastases by liposomes containing hydrophilic or lipophilic muramyl dipeptide. Immunopharmacology 2: 253

    Google Scholar 

  17. Fidler IJ, Fogler WE, Kleinerman ES, Saiki I (1985) Abrogation of species specificity for activation of tumoricidal properties in macrophages by recombinant mouse or human gamma interferon encapsulated in liposomes. J Immunol 135: 4289

    Google Scholar 

  18. Fidler IJ, Jessup JM, Fogler WE, Staerkel R, Mazumder A (1986) Activation of tumoricidal properties in peripheral blood monocytes of patients with colorectal carcinoma. Cancer Res 44: 994

    Google Scholar 

  19. Fidler IJ, Fan D, Ichinose Y (1989) Potent in situ activation of murine lung macrophages and therapy of melanoma metastases by systemic administration of liposomes containing muramyltripeptide phosphatidylethanolamine and interferon gamma. Invasion Metastasis 9: 75

    Google Scholar 

  20. Fidler IJ, Nii A, Utsugi T, Brown D, Bakouche O, Kleinerman ES (1990) Differential release of TNF-α, IL-1, and PGE2 by human blood monocytes subsequent to interaction with different bacterial derived agents. Lymphokine Res 9: 449

    Google Scholar 

  21. Fogler WE, Fidler IJ (1984) Modulation of the immune response by muramyl dipeptide. In: Chirigos MA, Fenichel RL (eds) Immune modulation agents and their mechanisms. Dekker, New York, p 499

    Google Scholar 

  22. Fogler WE, Fidler IJ (1986) The activation of tumoricidal properties in human blood monocytes by muramyl dipeptide requires specific intracellular interaction. J Immunol 136: 2311

    Google Scholar 

  23. Fogler WE, Wade R, Brundish DE, Fidler IJ (1985) Distribution and fate of free and liposome-encapsulated [3H]nor-muramyl dipeptide and [3H]muramyl tripeptide phosphatidylethanolamine in mice. J Immunol 135: 1372

    Google Scholar 

  24. Gisler RH, Dietrich FM, Baschang G, Brownbill A, Schumann G, Staber FB, Tarcsay L (1979) New developments in drugs enhancing the immune response: activation of lymphocytes and accessory cells by muramyl peptides. In: Turk JL, Danker D (eds) Immune responsiveness. MacMillan, London, p 133

    Google Scholar 

  25. Heicappell R, Naito S, Ichinose Y, Creasy AA, Lin LS, Fidler IJ (1987) Cytostatic and cytolytic effects of human recombinant tumor necrosis factor on human renal cell carcinoma cell lines derived from a single surgical specimen. J Immunol 138: 1634

    Google Scholar 

  26. Hibbs JB, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role forl-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235: 473

    Google Scholar 

  27. Hudson MM, Snyder JS, Jaffe N, Kleinerman ES (1988) In vitro and in vivo effect of Adriamycin therapy on monocyte activation by liposome-encapsulated immunomodulators. Cancer Res 48: 5256

    Google Scholar 

  28. Hume DA, Gordon S (1983) Optimal conditions for proliferation of bone marrow-derived mouse macrophages in culture: the roles of CSF-1, serum, Ca2+, and adherence. J Cell Physiol 117: 189

    Google Scholar 

  29. Hume DA, Allan W, Golder J, Stephens RW, Dow WF, Warren HS (1985) Preparation and characterization of human bone marrow-derived macrophages. J Leukocyte Biol 38: 541

    Google Scholar 

  30. Ichinose Y, Bakouche O, Tsao JY, 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

    Google Scholar 

  31. Ichinose Y, Tsao JY, 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

    Google Scholar 

  32. Kaplow LS (1965) Simplified myeloperosidase stain using benzidine dihydrochloride. Blood 26: 215

    Google Scholar 

  33. Keller R, Geiges M, Keist R (1990)l-Arginine-dependent reactive nitrogen intermediates as mediators of tumor cell killing by activated macrophages. Cancer Res 50: 1421

    Google Scholar 

  34. Kleinerman ES, Hudson MM (1989) Liposome therapy: a novel approach to the treatment of childhood osteosarcoma. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the therapy of infectious diseases and cancer, new series, vol 89. Liss, New York, p 71

    Google Scholar 

  35. Kleinerman ES, Fogler WE, Fidler IJ (1985) Intracellular activation of human and rodent macrophages by human lymphokines encapsulated in liposomes. J Leukocyte Biol 37: 571

    Google Scholar 

  36. Koff WC, Fidler IJ (1985) The potential use of liposome-mediated antiviral therapy. Antiviral Res 228: 495

    Google Scholar 

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

    Google Scholar 

  38. MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Howard PE (1989) Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 81: 935

    Google Scholar 

  39. Matsushima K, Taguchi M, Kovacs EJ, Young HA, Oppenheim JJ (1986) Intracellular localization of human monocyte associated interleukin 1 (IL-1) from monocytes by trypsin and plasmin. J Immunol 136: 2883

    Google Scholar 

  40. Mehta K, Lopez-Berestein G, Hersh EM, Juliano RL (1982) Uptake of liposomes and liposome-encapsulated muramyl dipeptide by human peripheral blood monocytes. J Reticuloendothelial Soc 1982: 155

    Google Scholar 

  41. Mourad N (1968) A simple method for obtaining platelet concentrations free of aggregates. Transfusion 8: 48

    Google Scholar 

  42. Murray JL, Kleinerman ES, Cunningham JE, Tatom JR, Andrejcio K, Lepe-Zuniga J, Lamki LM, Rosenblum MG, Frost H, Gutterman JU, Fidler IJ (1989) Phase I trial of liposomal muramyl-tripeptide-phosphatidylethanolamine [MTP-PE (CGP 19 835 A)] in cancer patients. J Clin Oncol 7: 915

    Google Scholar 

  43. Nathan CF (1987) Secretory products of macrophages. J Clin Invest 79: 319–327

    Google Scholar 

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

    Google Scholar 

  45. Onozaki K, Matsushima K, Aggarwal BB, Saito T, Oppenheim JJ (1985) Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol 135: 3862

    Google Scholar 

  46. Phillips NC, Tsao M (1989) Inhibition of experimental liver tumor growth in mice by liposomes containing a lipophilic muramyl dipeptide. Cancer Res 49: 936

    Google Scholar 

  47. Phillips NC, Mora ML, Chedid L, Lefrancier P, Bernard JM (1985) Activation of tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative. Cancer Res 45: 128

    Google Scholar 

  48. Poste G, Kirsh R, Fogler WE, Fidler IJ (1979) Activation of tumoricidal properties in mouse macrophages by lymphokines encapsulated in liposomes. Cancer Res 39: 881

    Google Scholar 

  49. Poste G, Bucana C, Raz A, Bugelski P, Kirsh R, Fidler IJ (1982) Analysis of the fate of systemically administered liposomes and implications for their use in drug delivery. Cancer Res 42: 1412

    Google Scholar 

  50. Poste G, Kirsh R, Bugelski P (1984) Liposomes as a drug delivery system in cancer therapy. In: Sunkara P (ed) Novel approaches to cancer chemotherapy. Academic Press, New York, p 323

    Google Scholar 

  51. Raz A, Fogler WE, Fidler IJ (1979) The effects of experimental conditions on the expression of in vitro mediated tumor cytotoxicity by murine macrophages. Cancer Immunol Immunother 7: 157

    Google Scholar 

  52. Raz A, Bucana C, Fogler WE, Poste G, Fidler IJ (1981) Biochemical, morphological, and ultrastructural studies on the uptake of liposomes by murine macrophages. Cancer Res 41: 487

    Google Scholar 

  53. Sanderson RJ, Shepperdson FT, Vatter AE, Talmadge DW (1977) Isolation and enumeration of peripheral blood monocytes. J Immunol 118: 1409

    Google Scholar 

  54. Schroit AJ, Fidler IJ (1982) Effects of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42: 161

    Google Scholar 

  55. Schroit AJ, Hart IR, Madsen J, Fidler IJ (1983) Selective delivery of drugs encapsulated in liposomes: natural targeting to macrophages involved in various disease states. J Biol Response Modif 2: 97

    Google Scholar 

  56. Sone S, Lopez-Berestein G, Fidler IJ (1986) Potentiation of direct cytotoxicity and production of tumor cytolytic factors in human blood monocytes by human recombinant interferon-gamma and muramyl dipeptide derivatives. Cancer Immunol Immunother 2: 93

    Google Scholar 

  57. Sone S, Tandon P, Utsugi T, Ogawara M, Shimizu E, Nii A, Ogura T (1986) Synergism of recombinant interferon gamma with liposome-encapsulated muramyl tripeptide in activation of the tumoricidal properties of human monocytes. Int J Cancer 38: 495

    Google Scholar 

  58. Sone S, Utsugi T, Tandon P, Ogawara M (1986) A dried preparation of liposomes containing muramyl tripeptide phosphatidylethanolamine as a potent activator of human blood monocytes to the antitumor state. Cancer Immunol 22: 191

    Google Scholar 

  59. Talmadge JE, Lenz BF, Klabansky R, Simon R, Riggs C, Guo S, Oldham RK, Fidler IJ (1986) Therapy of autochthonous skin cancers in mice with intravenously injected liposomes containing muramyl-tripeptide. Cancer Res 46: 1160

    Google Scholar 

  60. Turpin J, Hester JP, Hersh EM, Lopez-Berestein G (1986) Centrifugal elutriation as a method for isolation of large numbers of functionally intact human peripheral blood monocytes. J Clin Apheresis 3: 11

    Google Scholar 

  61. van Hoogevest P, Fankhauser P (1989) An industrial liposomal dosage form for muramyl-tripeptide-phosphatidylethanolamine (MTP-PE). In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the therapy of infectious diseases and cancer. Liss, New York, p 453

    Google Scholar 

  62. Yam LT, Li CY, Crosby WH (1971) Cytochemical identification of monocytes and granulocytes. Am J Clin Pathol 55: 283

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Utsugi, T., Nii, A., Fan, D. et al. Comparative efficacy of liposomes containing synthetic bacterial cell wall analogues for tumoricidal activation of monocytes and macrophages. Cancer Immunol Immunother 33, 285–292 (1991). https://doi.org/10.1007/BF01756592

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01756592

Key words

Navigation