Enhancement of Antitumor Resistance by Mycobacterial Products and Endotoxin

  • Edgar Ribi
  • John L. Cantrell
  • Kuni Takayama
  • Ken-ichi Amano


It has been more than 100 years since the suggestion was made that the control of cancer was mediated by immunologic methods. This hypothesis was based on the observation that tumors either partially or totally regressed in a few patients following an acute bacterial infection. In 1911, William Coley pioneered the study of mixed bacterial vaccines or their product known as “Coley’s toxin,” for treating cancers, and there is no doubt that these vaccines had some effect in many cases (Nauts et al., 1946). The effective ingredient appeared to be endotoxin, which caused hemorrhagic necrosis of the tumors. Thus, Gratia and Linz discovered in guinea pigs (1931) and Shwartzman and Michailovsky in mice (1932) that when animals with solid tumors are given single i.v. or i.p. inoculations with small doses of endotoxin, their tumors became hemorrhagic within 24 hr. This was originally done by analogy with the local Shwartzman reaction, with the idea that some hypothetical tumor virus might have prepared the site. It appeared that this type of tumor damage was mediated indirectly because little of the injected endotoxin would be likely to make contact with tumor cells, and would not exert any direct cytotoxicity in any case (Shapiro, 1940; Brailovsky et al., 1973).


Endotoxic Shock Toxic Fraction Cell Wall Skeleton Microscopic Lymph Node Metastasis Systemic Tumor Immunity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adam, A., Cirobaru, R., Ellouz, F., Petit, J.-F., and Lederer, E., 1974, Adjuvant activity of monomeric bacterial cell wall peptidoglycans, Biochem. Biophys. Res. Commun. 56:561.PubMedCrossRefGoogle Scholar
  2. Alexander, P., 1977, Back to the drawing board—The need for more realistic model systems for immunotherapy, Cancer 40:467.PubMedCrossRefGoogle Scholar
  3. Alexander, P., and Evans, R., 1971, Endotoxin and double-stranded RNA render macrophages cytotoxic, Nature New Biol. 232:76.PubMedGoogle Scholar
  4. Amano, K., Ribi, E., and Cantrell, J. L., 1982, Different structural requirements of endotoxic glycolipid for tumor regression and endotoxic activity, Biochem. Biophys. Res. Comm. 106:667.CrossRefGoogle Scholar
  5. Anacker, R. L., Barclay, W. R., Brehmer, W., Larson, C. L., and Ribi, E., 1967, Duration of immunity to tuberculosis in mice vaccinated intravenously with oil-treated cell walls of Mycobacterium bovis strain BCG, J. Immunol. 98:1265.PubMedGoogle Scholar
  6. Azuma, I., Ribi, E., Meyer, T. J., and Zbar, B., 1974, Biologically active components from mycobacterial cell walls. I. Isolation and composition of cell wall skeleton and P3, J. Natl. Cancer Inst. 52:95.PubMedGoogle Scholar
  7. Barclay, W. R., Anacker, R. L., Brehmer, W., and Ribi, E., 1967, Effects of oil-treated mycobacterial cell walls on the organs of mice, J. Bacteriol 94:1736.PubMedGoogle Scholar
  8. Berendt, M. J., North, R. J., and Kirsten, D. P., 1978, The immunological basis of endo-toxin-induced tumor regression: Requirement for T-cell-mediated immunity, J. Exp. Med. 148:1550.PubMedCrossRefGoogle Scholar
  9. Brailovsky, C., Trudel, M., Lallier, R., and Nigam, V. N., 1973, Growth of normal and transformed rat embryo fibroblasts: Effects of glycolipids from Salmonella minnesota R mutants, J. Cell Biol. 57:124.PubMedCrossRefGoogle Scholar
  10. Braun, V., Rehn, K., and Wolff, H., 1970, Supramolecular structure of the rigid layer of the cell wall of Salmonella, Serratia, Proteus, and Pseudomonas fluorescens: Number of lipoprotein molecules in a membrane layer, Biochemistry 9:5041.PubMedCrossRefGoogle Scholar
  11. Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., and Williamson, B., 1975, An endotoxin-induced serum factor that causes necrosis of tumors, Proc. Natl. Acad. Sci. USA 72:3666.PubMedCrossRefGoogle Scholar
  12. Chapman, H. A., Jr., and Hibbs, J. B., Jr., 1977, Modulation of macrophage tumoricidal capability by components of normal serum: A central role for lipid, Science 197:282.PubMedCrossRefGoogle Scholar
  13. Ellouz, F., Adam, A., Ciorbaru, R., and Lederer, E., 1974, Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives, Biochem. Biophys. Res. Commun. 59:1317.PubMedCrossRefGoogle Scholar
  14. Galanos, C., Lüderitz, O., and Westphal, O., 1969, A new method for the extraction of R lipopolysaccharides, Eur. J., Biochem. 9:245.CrossRefGoogle Scholar
  15. Granger, D. L., Yamamato, K., and Ribi, E., 1976, Delayed hypersensitivity and granulomatous response after immunization with protein antigens associated with a mycobacterial glycolipid and oil droplets,J. Immunol. 116:482.PubMedGoogle Scholar
  16. Gratia, A., and Linz, R., 1931, Le phénomène de Shwartzman dans la sarcome du cobaye, C. R. Soc. Biol. 108:427.Google Scholar
  17. Haskins, W. T., Landry, M., Milner, K. C., and Ribi, E., 1961, Biological properties of parent endotoxins and lipoid fractions, with a kinetic study of acid-hydrolyzed endotoxin, JExp. Med. 114:665.CrossRefGoogle Scholar
  18. Hausman, M. S., Snyderman, R., and Mergenhagen, S. E., 1972, Humoral mediators of Chemotaxis of mononuclear leukocytes, JInfect. Dis. 125:595.CrossRefGoogle Scholar
  19. Hibbs, J. B., Jr., Taintor, R. R., Chapman, H. A., Jr., and Weinberg, J. B., 1977, Macrophage tumor killing: Influence of the local environment, Science 197:279.PubMedCrossRefGoogle Scholar
  20. Hoffmann, M. K., Green, S., Old, L. J., and Oettgen, H. F., 1976, Serum containing en-dotoxin-induced tumour necrosis factor substitutes for helper T cells, Nature (London) 263:416.CrossRefGoogle Scholar
  21. Johnson, A. G., and Nowotny, A., 1964, Relationship of structure to function in bacterial O antigens. III. Biological properties of endotoxins, JBacteriol. 87:809.Google Scholar
  22. Joiner, K. A., and Wolff, S. M., 1981, The role of endotoxin in human disease and its therapy, in: Augmenting Agents in Cancer Therapy (Hersh, E. M, Chirigos, M. A., and M. J. Mastrangclo, eds.), pp. 125–134, Raven Press, New York.Google Scholar
  23. Kelly, M. T., McLaughlin, C. A., and Ribi, E., 1978, Eradication of microscopic lymph node metastases of the guinea pig line 10 tumor after intralesional injection of endotoxin plus mycobacterial components, Cancer Immunol. Immunother. 4:29.CrossRefGoogle Scholar
  24. Kleinschuster, S. J., Rapp, H. J., Leukcr, D. C., and Kainer, R. A., 1977, Regression of bovine ocular carcinoma by treatment with a mycobacterial vaccine, J. Satl. Cancer Inst. 58:1807.Google Scholar
  25. Kotani, S., Watanabe, Y., Kinoshita, F., Shimono, T., Morisaki, T., Shiba, T., Kusumoto, S., Tarumi, Y., and Ikenaka, K., 1975, Immunoadjuvant activities of synthetic S-acetylmuramylpeptides or amino acids, Biken J. 18:105.PubMedGoogle Scholar
  26. Lüderitz, O., Galanos, C., Lehmann, V., Norminen, M., Rietschel, E. T., Rosenfelder, G., Simon, M., and Westphal, O., 1973, Lipid A: Chemical structure and biological activity, JInfect. Dis. 128(Suppl.):17.CrossRefGoogle Scholar
  27. Lüderitz, O., Galanos, C., Lehmann, V., Mayer, H., Rietschel, E. T., and Weckesser, J., 1978, Chemical structure and biological activities of lipid A’s from various bacterial families, Saturwissenschaften 65:578.CrossRefGoogle Scholar
  28. Mclntire, F. C., Hargie, M. P., Schenck, J. R., Finley, R. A., Sievert, H. W., Rietschel, E. T., and Rosenstreich, D. L., 1976, Biologic properties of nontoxic derivatives of lipo-polysaccharide from Escherichia coli K235, J. Immunol. 117:674.Google Scholar
  29. McLaughlin, C. A., Bickel, W. D., Kyle, J. S., and Ribi, E., 1978, Synergistic tumor-regressive activity observed following treatment of line-10 heptocellular carcinomas with deproteinized BCG cell walls and mutant Salmonella typhimunum glycolipid, Cancer Immunol. Immunother. 5:45.CrossRefGoogle Scholar
  30. Merser, C., Sinay, P., and Adam, A., 1975, Total synthesis and adjuvant activity of bacterial peptidoglycan derivatives, Bwchem. Biophys. Res. Commun. 66:1316.CrossRefGoogle Scholar
  31. Meyer, R. J., Ribi, E., Azuma, I., and Zbar, B., 1974, Biologically active components from mycobacterial cell walls. II. Suppression and regression of strain-2 guinea pig hepatoma, J. Natl. Cancer Inst. 52:103.PubMedGoogle Scholar
  32. Milner, K. C., and Finkelstein, R. A., 1966, Bioassay of endotoxin: Correlation between pyrogenicity for rabbits and lethality for chick embryos, JInfect. Dis. 116:529.CrossRefGoogle Scholar
  33. Milner, K. C., Rudbach, J. A., and Ribi, E., 1971, Bacterial endotoxins: General characteristics, in: Microbial Toxins: A Comprehensive Treatise (G. Weinbaum, S. Kadis, and S. J. Ajl, eds.), pp. 1–65, Academic Press, New York.Google Scholar
  34. Nakae, T., 1976, Identification of the outer membrane proteins of E. coli that produce transmembrane channels in reconstituted vesicle membranes, Biochem. Biophys. Res. Commun. 71:877.PubMedCrossRefGoogle Scholar
  35. Nauts, H. C., Swift, W. E., and Coley, B. L., 1946, The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M. D., reviewed in the light of modern research, Cancer Res. 6:205.PubMedGoogle Scholar
  36. Nowotny, A., 1963a, Endotoxoid preparations, Nature (London) 197:721.CrossRefGoogle Scholar
  37. Nowotny, A., 1963b, Relation of structure to function in bacterial O-antigens. II. Fractionation of lipids present in Boivin-type endotoxin of Serratia marcescens, J. Bactenol. 85:427.Google Scholar
  38. Okuyama, H., Onoc, K., Takeda, J., and Morikawa, K., 1976, Histological studies on the adjuvanticity of BCG-cell wall, Recent Adv. RES Res. 16:67.Google Scholar
  39. Perrault, A., and Shear, M. J., 1949, Ehe bacterial cell of 5. marcescens as a source of tu-mor-necrotising polysaccharide, Cancer Res. 9:626.Google Scholar
  40. Rapp, H. J., 1973, A guinea pig model for tumor immunology: A summary, Isr. J. Med. Sci. 9:366.PubMedGoogle Scholar
  41. Ribi, E., Milner, K. C., and Perrine, T. D., 1959, Endotoxic and antigenic fractions from the cell wall of Salmonella ententidis: Methods for separation and some biologic activities, J. Immunol. 82:75.PubMedGoogle Scholar
  42. Ribi, E., Haskins, W. T., Eandy, M., and Milner, K. C., 1961, Preparation and host-reactive properties of endotoxin with low content of nitrogen and lipid, JExp. Med. 114: 647.CrossRefGoogle Scholar
  43. Ribi, E., Anacker, R. L., Brown, R., Haskins, W. T., Malmgren, B., Milner, K. C., and Rudbach, J. A., 1966a, Reaction of endotoxin and surfactants. I. Physical and biological properties of endotoxin treated with sodium deoxycholate, J. Bactenol. 92:1493.Google Scholar
  44. Ribi, E., Larson, C., Wicht, W., List, R., and Goode, G., 1966b, Effective nonliving vaccine against experimental tuberculosis in mice, J. Bactenol. 91:975.Google Scholar
  45. Ribi, E., Anacker, R. L., Barclay, W. R., Brehmer, W., Harris, S. C., Leif, W. R., and Simmons, J., 1971, Efficacy of mycobacterial cell walls as a vaccine against airborne tuberculosis in the rhesus monkey, JInfect. Dis. 123:527.CrossRefGoogle Scholar
  46. Ribi, E., Parker, R., and Milner, K. C., 1974, Microparticulate gel chromatography accelerated by centrifugal force and pressure, Methods Biochem. Anal. 22:355.PubMedCrossRefGoogle Scholar
  47. Ribi, E., Granger, D. L., Milner, K. C., and Strain, S. M., 1975, Brief communication: Tumor regression caused by endotoxins and mycobacterial fractions, J. Natl. Cancer Inst. 55:1253.PubMedGoogle Scholar
  48. Ribi, E., Milner, K. C., Granger, D. L., Kelly, M. T., Yamamoto, K., Brehmer, W., Parker, R., Smith, R. F., and Strain, S. M., 1976a, Immunotherapy with nonviable microbial components, Ann. NY. Acad. Sci. 277:228.PubMedCrossRefGoogle Scholar
  49. Ribi, E., Milner, K. C., Kelly, M. T., Granger, D. L., Yamamoto, K., McLaughlin, C. A., Brehmer, W., Strain, S. M., Smith, R. F., and Parker, R., 1976b, Structural requirements of microbial agents for immunotherapy of the guinea pig line-10 tumor, in: BCC in Cancer Immunotherapy (G. Lamoureux, R. Turcotte, and V. Portelance, eds.), pp. 51–61, Grüne Sc Stratton, New York.Google Scholar
  50. Ribi, E., McLaughlin, G. A., Gantrell, J. L., Brehmer, W., Azuma, I., Yamamura, Y., Strain, S. M., Hwang, K. M., and Toubiana, R., 1978, Immunotherapy for tumors with microbial constituents or their synthetic analogues: A review, in: Immunotherapy of Human Cancer, pp. 131–154, Raven Press, New York.Google Scholar
  51. Ribi, E., Parker, R., Strain, S. M., Mizuno, Y., Nowotny, A., Von Eschen, K. B., Cantrell, J. L., McLaughlin, G. A., Hwang, K. M., and Goren, M. B., 1979a, Peptides as requirement for immunotherapy of the guinea pig line-10 tumor with endotoxins, Cancer Immunol. Immunother. 7:43.CrossRefGoogle Scholar
  52. Ribi, E., Gantrell, J. L., Von Eschen, K., and Schwartzman, S., 1979b, Enhancement of endotoxic shock by adjuvant dipeptide (MDP), Cancer Res. 39:4756.PubMedGoogle Scholar
  53. Ribi, E., Gantrell, J. L., Schwartzman, S. M., and Parker, R., 1981, BCG cell wall skeleton, P3, MDP and other microbial components — Structure activity studies in animals models, in: Augmenting Agents in Cancer Therapy (E. M. Hersh, M. A. Chirigos, and M.J. Mastrangelo, eds.), pp. 15–31, Raven Press, New York.Google Scholar
  54. Ribi, E., Amano, K., Gantrell, J., Schwartzman, S., Parker, R., and Takayama, K., 1982, Preparation and anti-tumor activity of nontoxic lipid A, Cancer Immunol. Immunother. 12:91.CrossRefGoogle Scholar
  55. Richman, S. P., Gutterman, J. U., Hersh, E. M., and Ribi, E., 1978, Phase I-II study of intratumor immunotherapy with BCG cell wall skeleton plus P3, Cancer Immunol. Immunother. 5:41.CrossRefGoogle Scholar
  56. Rosner, M. R., Tang, J. Y., Barzilay, I., and Khorana, H. G., 1979, Structure of the lipo-polysaccharide from Escherichia coli heptoseless mutant, J. Biol. Chem. 254:5906.PubMedGoogle Scholar
  57. Schenck, J. R., Hargie, M. P., Brown, M. S., Ebert, D. S., Yoo, A. L., and Mclntire, F. C., 1969, The enhancement of antibody formation by Escherichia coli lipopolysaccharide and detoxified derivatives, J. Immunol. 102:1411.PubMedGoogle Scholar
  58. Shapiro, C. J., 1940, The effect of a toxic carbohydrate complex from S. enteritidis on transplantable rat tumors in tissue culture, Am. J. Hyg. 31(Sect. B):114.Google Scholar
  59. Shwartzman, G., and Michailovsky, N., 1932, Phenomenon of local skin reactivity to bacterial filtrates in the treatment of mouse sarcoma 180, Proc. Soc. Exp. Biol, Med. 29: 737.Google Scholar
  60. Takayama, K., Ribi, E., and Cantrell, J. L., 1981, Isolation of a nontoxic lipid A fraction containing tumor regression activity, Cancer Res. 41:2654.PubMedGoogle Scholar
  61. Vosika, G. J., Schmidtke, J. R., Goldman, A., Ribi, E., Parker, R., and Gray, G. R., 1979a, Intralesional immunotherapy of malignant melanoma with Mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate, Cancer 44:495.PubMedCrossRefGoogle Scholar
  62. Vosika, G. J., Schmidtke, J. R., Goldman, A., Parker, R., Ribi, E., and Gray, G. R., 1979b, Phase I–II study of intralesional immunotherapy with oil attached Mycobacterium smegmatis cell wall skeleton and trehalose dimycolate, Cancer Immunol. Immunother. 6:135.CrossRefGoogle Scholar
  63. Westphal, O., and Lüderitz, O., 1954, Chemische Erforschung von Lipopolysacchariden gram negativer Bakterien, Angew. Chem. 66:407.CrossRefGoogle Scholar
  64. Zbar, B., Bernstein, I. D., and Rapp, H. J., 1971, Suppression of tumor growth at the site of infection with living Bacillus Calmette-Guérin, J. Natl. Cancer Inst. 46:831.PubMedGoogle Scholar
  65. Zbar, B., Ribi, E., and Rapp, H. J., 1973, An experimental model for immunotherapy of cancer, Natl. Cancer Inst. Monogr. 39:3.PubMedGoogle Scholar
  66. Zbar, B., Ribi, E., Kelly, M., Granger, D., Evans, C., and Rapp, H. J., 1976, Immunologic approaches to the treatment of human cancer based on a guinea pig model, Cancer Immunol. Immunother. 1:127.CrossRefGoogle Scholar
  67. Zbar, B., Canti, G., Ashley, M. P., Rapp, H. J., Hunter, J. T., and Ribi, E., 1979, Eradication by immunization with mycobacterial vaccines and tumor cells of microscopic metastases remaining after surgery, Cancer Res. 39:1597.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Edgar Ribi
    • 1
  • John L. Cantrell
    • 1
  • Kuni Takayama
    • 2
  • Ken-ichi Amano
    • 3
  1. 1.Ribi ImmunoChem Research, Inc.HamiltonUSA
  2. 2.William S. Middleton Memorial Veterans HospitalMadisonUSA
  3. 3.Department of BacteriologyHirosaki University School of MedicineHirosaki 036Japan

Personalised recommendations