Lipid A-Induced Responses In Vivo

  • Néjia Sassi
  • Catherine Paul
  • Amandine Martin
  • Ali Bettaieb
  • Jean-François JeanninEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 667)


The lipid A analogs used in preclinical studies and clinical trials are not naturally-occurring forms of lipid A; they are synthetic molecules produced to be less toxic than lipid A itself and they do not reproduce the effects of natural lipid A molecules especially in vivo. The responses induced by lipid A analogs are summarized in this chapter: their fate in the blood stream and their toxicity as well as the lipid A tolerance and the tumor immune responses they induce. Lipid A is not found in the mammalian organism under normal circumstances so its use in cancer therapy raises important questions as to its different effects in vivo and its toxicity, particularly in cancer patients. Lipid A has to be injected intravenously (i.v.) to study its effects. Injections of chemically synthesized lipid A in humans and in animals produce sepsis symptoms, such as tachycardia, tachypnea, hyper or hypothermia and leukocytosis or leukopenia. Similar manifestations are observed after injection of purified lipopolysaccharide (LPS), which is why lipid A is usually thought of as the active part of LPS. While lipid A injection is therefore expected to induce reactions similar to septic shock, the lipid A molecules used to treat cancer are not natural forms but analogs, produced by chemical synthesis or genetic engineering, specifically selected for their low toxicity. The in vivo effects of such low-toxicity lipid A analogs are summarized in this chapter.


Nitric Oxide Major Histocompatibility Complex Class Antitumor Effect Adaptive Immune Response Peritoneal Macrophage 
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  1. 1.
    Rossignol DP, Wasan KM, Choo E et al. Safety, pharmacokinetics, pharmacodynamics and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 2004; 48(9):3233–3240.PubMedCrossRefGoogle Scholar
  2. 2.
    Hampton RY, Golenbock DT, Penman M et al. Recognition and plasma clearance of endotoxin by scavenger receptors. Nature 1991; 352(6333):342–344.PubMedCrossRefGoogle Scholar
  3. 3.
    Hopf U, Ramadori G, Moller B et al. Hepatocellular clearance function of bacteriallipopolysaccharides and free lipid A in mice with endotoxic shock. Am J Emerg Med 1984; 2(1):13–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Munford RS, Andersen JM, Dietschy JM. Sites of tissue binding and uptake in vivo of bacterial lipopolysaccharide-high density lipoprotein complexes: studies in the rat and squirrel monkey. J Clin Invest 1981; 68(6):1503–1513.PubMedCrossRefGoogle Scholar
  5. 5.
    Kleine B, Freudenberg MA, Galanos C. Excretion of radioactivity in faeces and urine of rats injected with 3H, 14C-lipopolysaccharide. Br J Exp Pathol 1985; 66(3):303–308.PubMedGoogle Scholar
  6. 6.
    Erwin AL, Munford RS. Deacylation of structurally diverse lipopolysaccharides by human acyloxyacyl hydrolase. J Biol Chem 1990; 265(27):16444–16449.PubMedGoogle Scholar
  7. 7.
    Bentala H, Verweij WR, Huizinga-Van der Vlag A et al. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock 2002; 18(6):561–566.PubMedCrossRefGoogle Scholar
  8. 8.
    Reddy TS, Kishore V. Distribution and localization of monophosphoryl lipid A in selected tissues of the rat. Immunopharmacol Immunotoxicol 1996; 18(1):145–159.PubMedCrossRefGoogle Scholar
  9. 9.
    Tobias PS, Soldau K, Ulevitch RJ. Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. J Exp Med 1986; 164(3):777–793.PubMedCrossRefGoogle Scholar
  10. 10.
    Jiang Z, Hong Z, Guo W et al. A synthetic peptide derived from bactericidal/permeability-increasing protein neutralizes endotoxin in vitro and in vivo. Int Immunopharmacol 2004; 4(4):527–537.PubMedCrossRefGoogle Scholar
  11. 11.
    Appelmelk BJ, An JQ, Geerts M et al. Lactoferrin is a lipid A-binding protein. Infect Immun 1994; 62(6):2628–2632.PubMedGoogle Scholar
  12. 12.
    Miyake K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 2007; 19(1):3–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Azuma M, Matsuo A, Fujimoto Y et al. Inhibition of lipid A-mediated type I interferon induction by bactericidal/permeability-increasing protein (BPI). Biochem Biophys Res Commun 2007; 354(2):574–578.PubMedCrossRefGoogle Scholar
  14. 14.
    Gazzano-Santoro H, Meszaros K, Birr C et al. Competition between rBP123, a recombinant fragment of bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein for binding to LPS and gram-negative bacteria. Infect Immun 1994; 62(4):1185–1191.PubMedGoogle Scholar
  15. 15.
    Chodaczek G, Zimecki M, Lukasiewicz J et al. A complex of lactoferrin with monophosphoryl lipid A is an efficient adjuvant of the humoral and cellular immune response in mice. Med Microbiol Immunol 2006; 195(4):207–216.PubMedCrossRefGoogle Scholar
  16. 16.
    Lien E, Chow JC, Hawkins LD et al. A novel synthetic acyclic lipid A-like agonist activates cells via the lipopolysaccharide/toll-like receptor 4 signaling pathway. J Biol Chem 2001; 276(3):1873–1880.PubMedCrossRefGoogle Scholar
  17. 17.
    Rasool O, Freer E, Moreno E et al. Effect of Brucella abortus lipopolysaccharide on oxidative metabolism and lysozyme release by human neutrophils. Infect Immun 1992; 60(4):1699–1702.PubMedGoogle Scholar
  18. 18.
    Dunzendorfer S, Lee HK, Soldau K et al. Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses. FASEB J 2004; 18(10):1117–1119.PubMedGoogle Scholar
  19. 19.
    Feist W, Ulmer AJ, Musehold J et al. Induction of tumor necrosis factor-alpha release by lipopolysaccharide and defined lipopolysaccharide partial structures. Immunobiology 1989; 179(4–5):293–307.PubMedGoogle Scholar
  20. 20.
    Ogawa T, Suda Y, Kashihara W et al. Immunobiological activities of chemically defined lipid A from Helicobacter pylori LPS in comparison with Porphyromonas gingivalis lipid A and Escherichia coli-type synthetic lipid A (compound 506). Vaccine 1997; 15(15):1598–1605.PubMedCrossRefGoogle Scholar
  21. 21.
    Jeannin JF, Onier N, Lagadec P et al. Antitumor effect of synthetic derivatives of lipid A in an experimental model of colon cancer in the rat. Gastroenterology 1991; 101(3):726–733.PubMedGoogle Scholar
  22. 22.
    Kotani S, Takada H, Tsujimoto M et al. Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli remutant. Infect Immun 1985; 49(1):225–237.PubMedGoogle Scholar
  23. 23.
    Takahashi I, Kotani S, Takada H et al. Requirement of a properly acylated beta(1-6)-D-glucosamine disaccharide bisphosphate structure for efficient manifestation of full endotoxic and associated bioactivities of lipid A. Infect Immun 1987; 55(1):57–68.PubMedGoogle Scholar
  24. 24.
    Caroff M, Cavaillon JM, Fitting C et al. Inability of pyrogenic, purified Bordetella pertussis lipid A to induce interleukin-1 release by human monocytes. Infect Immun 1986; 54(2):465–471.PubMedGoogle Scholar
  25. 25.
    Hurme M, Serkkola E. Comparison of interleukin 1 release and interleukin 1 mRNA expression of human monocytes activated by bacterial lipopolysaccharide or synthetic lipid A. Scand J Immunol 1989; 30(2):259–263.PubMedCrossRefGoogle Scholar
  26. 26.
    Kotani S, Takada H, Takahashi I et al. Low endotoxic activities of synthetic Salmonella-type lipid A with an additional acyloxyacyl group on the 2-amino group of beta (1–6) glucosamine disaccharide 1, 4′-bisphosphate. Infect Immun 1986; 52(3):872–884.PubMedGoogle Scholar
  27. 27.
    Arata S, Kasai N, Klein TW et al. Legionella pneumophila growth restriction and cytokine production by murine macrophages activated by a novel Pseudomonas lipid A. Infect Immun 1994; 62(2):729–732.PubMedGoogle Scholar
  28. 28.
    Cavaillon JM, Fitting C, Caroff M et al. Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A. Infect Immun 1989; 57(3):791–797.PubMedGoogle Scholar
  29. 29.
    Okemoto K, Kawasaki K, Hanada K et al. A potent adjuvant monophosphoryl lipid A triggers various immune responses, but not secretion of IL-1beta or activation of caspase-1. J Immunol 2006; 176(2):1203–1208.PubMedGoogle Scholar
  30. 30.
    Martin M, Michalek SM, Katz J. Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A. Infect Immun 2003; 71(5):2498–2507.PubMedCrossRefGoogle Scholar
  31. 31.
    Salkowski CA, Detore GR, Vogel SN. Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon and interleukin-10 mRNA production in murine macrophages. Infect Immun 1997; 65(8):3239–3247.PubMedGoogle Scholar
  32. 32.
    Galanos C, Lehmann V, Luderitz O et al. Endotoxic properties of chemically synthesized lipid A part structures. Comparison of synthetic lipid A precursor and synthetic analogues with biosynthetic lipid A precursor and free lipid A. Eur J Biochem 1984; 140(2):221–227.PubMedCrossRefGoogle Scholar
  33. 33.
    Saha DC, Barua RS, Astiz ME et al. Monophosphoryl lipid A stimulated up-regulation of reactive oxygen intermediates in human monocytes in vitro. J Leukoc Biol 2001; 70(3):381–385.PubMedGoogle Scholar
  34. 34.
    Dahinden CA, Fehr J, Hugli TE. Role of cell surface contact in the kinetics of superoxide production by granulocytes. J Clin Invest 1983; 72(1):113–121.PubMedCrossRefGoogle Scholar
  35. 35.
    Chen YF, Solem L, Johnson AG. Activation of macrophages from aging mice by detoxified lipid A. J Leukoc Biol 1991; 49(4):416–422.PubMedGoogle Scholar
  36. 36.
    Dijkstra J, Mellors JW, Ryan JL. Altered in vivo activity of liposome-incorporated lipopolysaccharide and lipid A. Infect Immun 1989; 57(11):3357–3363.PubMedGoogle Scholar
  37. 37.
    Saha DC, Astiz ME, Lin RY et al. Monophosphoryl lipid A stimulated up-regulation of nitric oxide synthase and nitric oxide release by human monocytes in vitro. Immunopharmacology 1997; 37(2–3):175–184.PubMedCrossRefGoogle Scholar
  38. 38.
    Tanamoto K, Azumi S, Haishima Y et al. Endotoxic properties of free lipid A from Porphyromonas gingivalis. Microbiology 1997; 143(Pt1):63–71.PubMedCrossRefGoogle Scholar
  39. 39.
    Lopez-Urrutia L, Alonso A, Nieto ML et al. Lipopolysaccharides of Brucella abortus and Brucella melitensis induce nitric oxide synthesis in rat peritoneal macrophages. Infect Immun 2000; 68(3):1740–1745.PubMedCrossRefGoogle Scholar
  40. 40.
    Renzi PM, Lee CH. Anti-lipid A monoclonal antibodies alter human endothelial cell ICAM-1 expression in vitro. Shock 1995; 3(5):329–336.PubMedGoogle Scholar
  41. 41.
    Dahinden C, Galanos C, Fehr J. Granulocyte activation by endotoxin. I. Correlation between adherence and other granulocyte functions and role of endotoxin structure on biologic activity. J Immunol 1983; 130(2):857–862.PubMedGoogle Scholar
  42. 42.
    Kang BH, Manderschied BD, Huang YC et al. Contrasting response of lung parenchymal cells to instilled TNF alpha and IFN gamma: the inducibility of specific cell ICAM-1 in vivo. Am J Respir Cell Mol Biol 1996; 15(4):540–550.PubMedGoogle Scholar
  43. 43.
    Kotani S, Takada H, Tsujimoto M et al. Immunobiological activities of synthetic lipid A analogs and related compounds as compared with those of bacterial lipopolysaccharide, reglycolipid, lipid A and muramyl dipeptide. Infect Immun 1983; 41(2):758–773.PubMedGoogle Scholar
  44. 44.
    Tanamoto K, Zähringer U, McKenzie GR et al. Biological activities of synthetic lipid A analogs: pyrogenicity, lethal toxicity, anticomplement activity and induction of gelation of Limulus amoebocyte lysate. Infect Immun 1984; 44(2):421–426.PubMedGoogle Scholar
  45. 45.
    Ramsey RB, Hamner MB, Alving BM et al. Effects of lipid A and liposomes containing lipid A on platelet and fibrinogen production in rabbits. Blood 1980; 56(2):307–310.PubMedGoogle Scholar
  46. 46.
    Grabarek J, Timmons S, Hawiger J. Modulation of human platelet protein kinase C by endotoxic lipid A. J Clin Invest 1988; 82(3):964–971.PubMedCrossRefGoogle Scholar
  47. 47.
    Takada H, Kotani S, Tsujimoto M et al. Immunopharmacological activities of a synthetic counterpart of a biosynthetic lipid A precursor molecule and of its analogs. Infect Immun 1985; 48(1):219–227.PubMedGoogle Scholar
  48. 48.
    Verghese MW, Snyderman R. Endotoxin (LPS) stimulates in vitro migration of macrophages from LPS-resistant mice but not from LPS-sensitive mice. J Immunol 1982; 128(2):608–613.PubMedGoogle Scholar
  49. 49.
    Sagara-Ishijima N, Furuhama K. Toxic characteristics of the synthetic lipid A derivative DT-5461 in rats and monkeys. Toxicol Sci 1999; 49(2):324–331.PubMedCrossRefGoogle Scholar
  50. 50.
    Ismaili J, Rennesson J, Aksoy E et al. Monophosphoryl lipid A activates both human dendritic cells and T-cells. J Immunol 2002; 168(2):926–932.PubMedGoogle Scholar
  51. 51.
    Lapteva N, Seethammagari MR, Hanks BA et al. Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation. Cancer Res 2007; 67(21):10528–10537.PubMedCrossRefGoogle Scholar
  52. 52.
    De Becker G, Moulin V, Pajak B et al. The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells. Int Immunol 2000; 12(6):807–815.PubMedCrossRefGoogle Scholar
  53. 53.
    Pajak B, Garze V, Davies G et al. The adjuvant OM-174 induces both the migration and maturation of murine dendritic cells in vivo. Vaccine 2003; 21(9–10):836–842.PubMedCrossRefGoogle Scholar
  54. 54.
    Ten Brinke A, Karsten ML, Dieker MC et al. The clinical grade maturation cocktail monophosphoryl lipid A plus IFNgamma generates monocyte-derived dendritic cells with the capacity to migrate and induce Thl polarization. Vaccine 2007; 25(41):7145–7152.PubMedCrossRefGoogle Scholar
  55. 55.
    Thompson BS, Chilton PM, Ward JR et al. The low-toxicity versions of LPS, MPL adjuvant and RC529, are efficient adjuvants for CD4+ T-cells. J Leukoc Biol 2005; 78(6):1273–1280.PubMedCrossRefGoogle Scholar
  56. 56.
    Evans JT, Cluff CW, Johnson DA et al. Enhancement of antigen-specific-immunity via the TLR4 ligands MPL adjuvant and Ribi. 529. Expert Rev Vaccines 2003; 2(2):219–229.PubMedCrossRefGoogle Scholar
  57. 57.
    Baldridge JR, McGowan P, Evans JT et al. Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther 2004; 4(7):1129–1138.PubMedCrossRefGoogle Scholar
  58. 58.
    Kumazawa E, Tohgo A, Soga T et al. Significant antitumor effect of a synthetic lipid A analogue, DT-5461, on murine syngeneic tumor models. Cancer Immunol Immunother 1992; 35(5):307–314.PubMedCrossRefGoogle Scholar
  59. 59.
    Yang D, Satoh M, Veda H et al. Activation of tumor-infiltrating macrophages by a synthetic lipid A analog (ON0-4007) and its implication in antitumor effects. Cancer Immunol Immunother 1994; 38(5):287–293.PubMedCrossRefGoogle Scholar
  60. 60.
    Onier N, Hilpert S, Reveneau S et al. Expression of inducible nitric oxide synthase in tumors in relation with their regression induced by lipid A in rats. Int J Cancer 1999; 81(5):755–760.PubMedCrossRefGoogle Scholar
  61. 61.
    Vosika GJ, Barr C, Gilbertson D. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother 1984; 18(2):107–112.PubMedCrossRefGoogle Scholar
  62. 62.
    de Bono JS, Dalgleish AG, Carmichael J et al. Phase I study of ON0-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. Clin Cancer Res 2000; 6(2):397–405.PubMedGoogle Scholar
  63. 63.
    Ishida H, Fujii E, Irie K et al. Role of inHammatory mediators in lipid A analogue (ON0-4007)-induced vascular permeability change in mouse skin. Br J Pharmacol 2000; 130(6):1235–1240.PubMedCrossRefGoogle Scholar
  64. 64.
    Lam C, Schutze E, Hildebrandt J et al. SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis. Antimicrob Agents Chernother 1991; 35(3):500–505.Google Scholar
  65. 65.
    Ali KH, Feeley TW, Bieber M et al. Cardiovascular effect of intravenous lipid A in rabbits. Circ Shock 1987; 23(4):285–293.PubMedGoogle Scholar
  66. 66.
    Kiani A, Tschiersch A, Gaboriau E et al. Downreguladon of the proinHammatory cytokine response to endotoxin by pretreatment with the nontoxic lipid A analog SDZ MRL 953 in cancer patients. Blood 1997; 90(4):1673–1683.PubMedGoogle Scholar
  67. 67.
    Madonna GS, Peterson JE, Ribi EE et al. Early-phase endotoxin tolerance: induction by a detoxified lipid A derivative, monophosphoryl lipid A. Infect Immun 1986; 52(1):6–11.PubMedGoogle Scholar
  68. 68.
    Astiz ME, Rackow EC, Kim YB et al. Monophosphoryl lipid A induces tolerance to the lethal hemodynamic effects of endotoxemia. Circ Shock 1991; 33(2):92–97.PubMedGoogle Scholar
  69. 69.
    Zuckerman SH, Queshi N. In vivo inhibition of lipopolysaccharide-induced lethality and tumor necrosis factor synthesis by Rhodobacter sphaeroides diphosphoryl lipid A is dependent on corticosterone induction. Infect Immun 1992; 60(7):2581–2587.PubMedGoogle Scholar
  70. 70.
    Matsuura M, Kiso M, Hasegawa A et al. Multistep regulation mechanisms for tolerance induction to lipopolysaccharide lethality in the tumor-necrosis-factor-alpha-mediated pathway. Application of nontoxic monosaccharide lipid A analogues for elucidation of mechanisms. Eur J Biochem 1994; 221(1):335–341.PubMedCrossRefGoogle Scholar
  71. 71.
    Henricson BE, Benjamin WR, Vogel SN. Differential cytokine induction by doses of lipopolysaccharide and monophosphoryl lipid A that result in equivalent early endotoxin tolerance. Infect Immun 1990; 58(8):2429–2437.PubMedGoogle Scholar
  72. 72.
    Beutler B, Krochin N, Milsark IW et al. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 1986; 232(4753):977–980.PubMedCrossRefGoogle Scholar
  73. 73.
    Amano Y, Lee SW, Allison AC. Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta and interleukin-6: mediation by decreased mRNA stability. Mol Pharmacol 1993; 43(2):176–182.PubMedGoogle Scholar
  74. 74.
    Henricson BE, Perera PY, Qureshi N et al. Rhodopseudomonas sphaeroides lipid A derivatives block in vitro induction of tumor necrosis factor and endotoxin tolerance by smooth lipopolysaccharide and monophosphoryl lipid A. Infect Immun 1992; 60(10):4285–4290.PubMedGoogle Scholar
  75. 75.
    Galanos C, Luderitz O, Rietschel ET et al. Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities. Eur J Biochem 1985; 148(1):1–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Knopf HP, Otto F, Engelhardt R et al. Discordant adaptation of human peritoneal macrophages to stimulation by lipopolysaccharide and the synthetic lipid A analogue SDZ MRL 953. Down-regulation of TNF-alpha and IL-6 is paralleled by an up-regulation of lL-1 beta and granulocyte colony-stimulating factor expression. J Immunol 1994; 153(1):287–299.PubMedGoogle Scholar
  77. 77.
    Kitchens RL, Ulevitch RJ, Munford RS. Lipopolysaccharide (LPS) partial structures inhibit responses to LPS in a human macrophage cell line without inhibiting LPS uptake by a CD14-mediated pathway. J Exp Med 1992; 176(2):485–494.PubMedCrossRefGoogle Scholar
  78. 78.
    Carswell EA, Old LJ, Kassel RL et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72(9):3666–3670.PubMedCrossRefGoogle Scholar
  79. 79.
    van de Wiel PA, van der Pijl A, Bloksma N. Role of tumour necrosis factor in the tumour-necrotizing activity of agents with diverging toxicity. Cancer Immunol Immunother 1991; 33(2):115–120.PubMedCrossRefGoogle Scholar
  80. 80.
    Kuramitsu Y, Nishibe M, Ohiro Y et al. A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. Anticancer Drugs 1997; 8(5):500–508.PubMedCrossRefGoogle Scholar
  81. 81.
    Akimoto T, Kumazawa E, Jimbo T et al. Antitumor effect of DT-5461 a, a synthetic low-toxicity lipid A analog, involves endogenous tumor necrosis factor induction subsequent to macrophage activation. Int J Immunopharmacol 1994; 16(11):887–893.PubMedCrossRefGoogle Scholar
  82. 82.
    Sato K, Yoo YC, Mochizuki M et al. Inhibition of tumor-induced angiogenesis by a synthetic lipid A analogue with low endotoxicity, DT-5461. Jpn J Cancer Res 1995; 86(4):374–382.PubMedGoogle Scholar
  83. 83.
    Matsumoto N, Oida H, Aze Y et al. Intrarumoral tumor necrosis factor induction and tumor growth suppression by ONO-4007, a low-toxicity lipid A analog. Anticancer Res 1998; 18(6A):4283–4289.PubMedGoogle Scholar
  84. 84.
    Kumazawa E, Akimoto T, Kita Y et al. Intratumoral production of tumor necrosis factor augmented by endogenous interferons results in potent antitumor effects of DT-5461, a synthetic lipid A analog. J Immunother Emphasis Tumor Immunol 1995; 17(3):141–150.PubMedGoogle Scholar
  85. 85.
    Onier N, Hilpert S, Arnould L et al. Cure of colon cancer metastasis in rats with the new lipid A OM 174. Apoptosis of tumor cells and immunization of rats. Clin Exp Metastasis 1999; 17(4):299–306.PubMedCrossRefGoogle Scholar
  86. 86.
    Onier N, Lejeune P, Martin M et al. Involvement of T-lymphocytes in curative effect of a new immunomodulator OM 163 on rat colon cancer metastases. Eur J Cancer 1993; 29A(14):2003–2009.PubMedCrossRefGoogle Scholar
  87. 87.
    Dighe AS, Richards E, Old LJ et al. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1994; 1(6):447–456.PubMedCrossRefGoogle Scholar
  88. 88.
    Matsushita K, Kuramitsu Y, Ohiro Y et al. ONO-4007, a synthetic lipid A analog, induces Th1-type immune response in tumor eradication and restores nitric oxide production by peritoneal macrophages. Int J Oncol 2003; 23(2):489–493.PubMedGoogle Scholar
  89. 89.
    Hibbs JB jr, Taintor RR, Vavrin Z et al. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 1988; 157(1):87–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Jeannin JF, Leon L, Cortier M et al. Nitric oxide-induced resistance or sensitization to death in tumor cells. Nitric Oxide 2008; 19(2):158–163.PubMedCrossRefGoogle Scholar
  91. 91.
    Lejeune P, Lagadec P, Onier N et al. Nitric oxide involvement in tumor-induced immunosuppression. J Immunol 1994; 152(10):5077–5083.PubMedGoogle Scholar
  92. 92.
    Larmonier CB, Arnould L, Larmonier N et al. Kinetics of tumor cell apoptosis and immune cell activation during the regression of tumors induced by lipid A in a rat model of colon cancer. Int J Mol Med 2004; 13(3):355–361.PubMedGoogle Scholar
  93. 93.
    Lagadec P, Raynal S, Lieubeau B et al. Evidence for control of nitric oxide synthesis by intracellular transforming growth factor-beta1 in tumor cells. Implications for tumor development. Am J Pathol 1999; 154(6):1867–1876.PubMedGoogle Scholar
  94. 94.
    Gauthier N, Lohm S, Touzery C et al. Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs. Carcinogenesis 2004; 25(9):1559–1565.PubMedCrossRefGoogle Scholar
  95. 95.
    Alexander P, Evans R. Endotoxin and double stranded RNA render macrophages cytotoxic. Nat New Biol 1971; 232(29):76–78.PubMedGoogle Scholar
  96. 96.
    Satoh M, Ando S, Shinoda T et al. Clearance of bacteriallipopolysaccharides and lipid A by the liver and the role of argininosuccinate synthase. Innate Immun 2008; 14(1):51–60.PubMedCrossRefGoogle Scholar
  97. 97.
    Verreck FA, de Boer T, Langenberg DM et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA 2004; 101(13):4560–4565.PubMedCrossRefGoogle Scholar
  98. 98.
    Nakatsuka M, Kumazawa Y, Homma JY et al. Inhibition in mice of experimental metastasis of B16 melanoma by the synthetic lipid A-subunit analogue GLA-60. Int J Immunopharmacol 1991; 13(1):11–19.PubMedCrossRefGoogle Scholar
  99. 99.
    Takahashi M, Ogasawara K, Takeda K et al. LPS induces NK1.1+ alpha beta T-cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells. J Immunol 1996; 156(7):2436–2442.PubMedGoogle Scholar
  100. 100.
    D’Agostini C, Pica F, Febbraro G et al. Antitumour effect of OM-174 and cyclophosphamide on murine B16 melanoma in different experimental conditions. Int Immunopharmacol 2005; 5(7–8):1205–1212.PubMedCrossRefGoogle Scholar
  101. 101.
    Bhardwaj N. Processing and presentation of antigens by dendritic cells: implications for vaccines. Trends Mol Med 2001; 7(9):388–394.PubMedCrossRefGoogle Scholar
  102. 102.
    Parr I, Wheeler E, Alexander P. Similarities of the anti-tumour actions of endotoxin, lipid A and double-stranded RNA. Br J Cancer 1973; 27(5):370–389.PubMedGoogle Scholar
  103. 103.
    Andreani V, Gatti G, Simonella L et al. Activation of Toll-like receptor 4 on tumor cells in vitro inhibits subsequent tumor growth in vivo. Cancer Res 2007; 67(21):10519–10527.PubMedCrossRefGoogle Scholar
  104. 104.
    Matsushita K, Kobayashi M, Totsuka Y et al. ONO-4007 induces specific anti-tumor immunity mediated by tumor necrosis factor-alpha. Anticancer Drugs 1998; 9(3):273–282.PubMedCrossRefGoogle Scholar
  105. 105.
    Matsumoto N, Aze Y, Akimoto A et al. Restoration of immune responses in tumor-bearing mice by ONO-4007, an antitumor lipid A derivative. Immunopharmacology 1997; 36(1):69–78.PubMedCrossRefGoogle Scholar
  106. 106.
    Akimoto T, Kumazawa E, Jimbo T et al. DT-5461a, an antitumor synthetic lipid a analog, causes selective blood flow reduction in tumor tissue. Anticancer Res 1995; 15(1):105–107.PubMedGoogle Scholar
  107. 107.
    Jimbo T, Akimoto T, Tohgo A. Systemic administration of a synthetic lipid A derivative, DT-5461a, reduces tumor blood flow through endogenous TNF production in hepatic cancer model of VX2 carcinoma in rabbits. Anticancer Res 1996; 16(1):359–364.PubMedGoogle Scholar
  108. 108.
    Saiki I, Sato K, Yoo YC et al. Inhibition of tumor-induced angiogenesis by the administration of recombinant interferon-gamma followed by a synthetic lipid-A subunit analogue (GLA-60). Int J Cancer 1992; 51(4):641–645.PubMedCrossRefGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Néjia Sassi
    • 1
  • Catherine Paul
    • 1
  • Amandine Martin
    • 1
  • Ali Bettaieb
    • 2
  • Jean-François Jeannin
    • 2
    Email author
  1. 1.Tumor Immunology and Immunotherapy Laboratory Inserm U866University of BurgundyDijonFrance
  2. 2.Tumor Immunology and Immunotherapy Laboratory Ecole Practique des Hautes Etudes Inserm U866University of BurgundyDijonFrance

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