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Parallel antitumor, granuloma-forming and tumor-necrosis-factor-priming activities of mycoloyl glycolipids fromNocardia rubra that differ in carbohydrate moiety: Structure—activity relationships

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Summary

Multiple intravenous injections (30 µg, ten times) in ICR mice of trehalose dimycolate and glucose monomycolate fromNocardia rubra, containing C36–48 mycolic acids, showed a prominent antitumor effect on a subcutaneously implanted sarcoma-180, an allogeneic sarcoma of mice with a significant granuloma formation in lungs, spleen and liver. On the other hand, mycoloyl glycolipids other than glucose monomycolate and trehalose dimycolate, such as mannose or fructose mycolate, showed no significant activity for tumor regression or granuloma formation in mice.

Trehalose dimycolate and glucose monomycolate fromN. rubra, and glucose monomycolate with C56–60 mycolic acids fromRhodococcus terrae also showed a distinctive priming activity for tumor necrosis factor (TNF), when lipopolysaccharide fromEscherichia coli was administered as an eliciting agent. The TNF activity in the sera of mice was abrogated almost completely by anti-(murine TNFα) antibody with protein-A—agarose. Again in contrast, mannose and fructose mycolate fromN. rubra and glucose monomycolate with C30–34 mycolic acids fromRhodococcus equi did not show such activities in mice.

Meth-A, a syngeneic fibrosarcoma of BALB/c mice, was less sensitive to administration of glycolipids than sarcoma-180. These results indicated that the existence of a glucose or trehalose molecule was necessary for the expression of immunomodifying activities among various mycoloyl glycolipids differing in carbohydrate structure. However, since the administration of lipopolysaccharide was essentially required as an eliciting agent for the induction of TNF, while no eliciting agent was required for the antitumor activities, TNF does not seem to contribute directly to the antitumor activities of mycoloyl glycolipids in our systems. There was, however, a parallel structure-activity relationship among granuloma-forming, antitumor and TNF-priming activities, indicating that the structures of both the carbohydrate moiety and the mycoloyl residues influenced an initial step, such as macrophage activation, commonly and profoundly.

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References

  1. Aggarwal BB, Kohr WJ, Hass PE, Moffat B, Spencer SA, Henzel WJ, Bringman TS, Nedwin GE, Goeddel DV, Harkins RN (1985) Human tumor necrosis factor. J Biol Chem 260: 2345

    Google Scholar 

  2. Bekierkunst A (1976) Immunotherapy of cancer with nonliving mycobacteria and cord factor (trehalose-6,6′-dimycolate) in aqueous medium. J Natl Cancer Inst 57: 963

    Google Scholar 

  3. Bekierkunst A, Levij IS, Yarkoni E, Vilkas E, Adam A, Lederer E (1969) Granuloma formation induced in mice by chemically defined mycobacterial fractions. J Bacteriol 100: 95

    Google Scholar 

  4. Bekierkunst A, Levij IS, Yarkoni E, Vilkas E, Lederer E (1971) Suppression of urethan-induced lung adenomas in mice treated with trehalose-6,6-dimycolate (cord factor) and living Bacillus Calmette-Guérin. Science 174: 1240

    Google Scholar 

  5. Bekierkunst A, Wang L, Toubiana R, Lederer E (1974) Immunotherapy of cancer with non-living BCG and fractions derived from mycobacteria: role of cord factor (trehalose6,6′-dimycolate) in tumor regression. Infect Immun 10: 1044

    Google Scholar 

  6. Beutler B, Cerami A (1986) Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 320: 584

    Google Scholar 

  7. Beutler BA, Milsark IW, Cerami A (1985) Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 135: 3972

    Google Scholar 

  8. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72: 3666

    Google Scholar 

  9. Chihara G, Hamuro J, Maeda YY, Arai Y, Fukuoka F (1970) Fractionation and purification of polysaccharides with marked antitumor activity, especially lentinan, fromLentinus edodes (Berk.) Sing. (an edible mushroom). Cancer Res 30: 2776

    Google Scholar 

  10. Havell EA, Fiers W, North RJ (1988) The antitumor function of tumor necrosis factor (TNF). I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med 167: 1067

    Google Scholar 

  11. Kaneda K, Sumi Y, Kurano F, Kato Y, Yano I (1986) Granuloma formation and hemopoiesis induced by C36–48-mycolic-acid-containing glycolipids fromNocardia rubra. Infect Immun 54: 869

    Google Scholar 

  12. Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P (1989) The inducing role of tumor necrosis factor in the development of bacterial granulomas during BCG infection. Cell 56: 731

    Google Scholar 

  13. Kurano S, Sugimoto N, Sumi Y, Sawai H, Kato Y, Kaneda K, Yano I (1987) Newly isolated glycolipids fromRhodococcus terrae cell wall and their granuloma forming activities. Yakugaku Zasshi 107: 46

    Google Scholar 

  14. Lepoivre M, Tenu JP, Lemaire G, Petit JF (1982) Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters. J Immunol 129: 860

    Google Scholar 

  15. Mannel DN, Moore RN, Mergenhagen SE (1980) Macrophages as a sorce of tumoricidal activity (tumor-necrotizing factor). Infect Immun 20: 523

    Google Scholar 

  16. Meyer TJ, Ribi EE, Azuma I, 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

    Google Scholar 

  17. Niitsu Y, Watanabe N, Sone H, Neda H, Urushizaki I (1985) T cell involvement in production of tumor necrosis factor: reconstitution experiments with nude mice. Jpn J Cancer Res 76: 395

    Google Scholar 

  18. North RJ, Edward AH (1988) The antitumor function of tumor necrosis factor (TNF). II. Analysis of the role of endogenous TNF in endotoxin-induced hemorrhadic necrosis and regression of an established sarcoma. J Exp Med 167: 1086

    Google Scholar 

  19. Oka S, Natsuhara Y, Kato Y, Kaneda K, Tomiyasu I, Yano I (1988) Structure analysis and macrophage activating ability of mycolic acid-containing glycolipids in Actinomycetales. In: Proceedings for 23th Joint Conference on Tuberculosis. The US/Japan Cooperative Medical Science Program, p 3

  20. Old LJ (1985) Tumor necrosis factor (TNF). Science 230: 630

    Google Scholar 

  21. Oldman RK (1983) Biological response modifiers. J Natl Cancer Inst 70: 789

    Google Scholar 

  22. Orbach-Arbouys S, Tenu JP, Petit JF (1983) Enhancement of in vitro and in vivo antitumor activity by cord factor (6-6′-dimycolate of trehalose) administered suspended in saline. Int Arch Allergy Appl Immunol 71: 67

    Google Scholar 

  23. Ribi EE, Granger DL, Milner KC, Strain SM (1975) Tumor regression caused by endotoxin and mycobacterial fractions. J Natl Cancer Inst 55: 1253

    Google Scholar 

  24. Ribi E, Takayama K, Milner K, Gray GR, Goren M, Parker R, MacLaughlin Ch, Kelly M (1976) Regression of tumors by an endotoxin combined with trehalose mycolates of differing structure. Cancer Immunol Immunother 1: 265

    Google Scholar 

  25. Ruff MR, Gifford GF (1980) Purification and physico-chemical characterization of rabbit tumor necrosis factor. J Immunol 125: 1671

    Google Scholar 

  26. Satomi N, Haranaka K, Kunii O (1981) Research on the production of tumor necrosis factor (TNF). Jpn J Exp Med 51: 317

    Google Scholar 

  27. Sawai H, Sumi Y, Kurano S, Gondaira S, Kato Y, Tomiyasu I, Imaizumi S, Kaneda K, Yano I (1987) Granuloma formation by glycolipids containing mycolic acid inNocardia, Rhodococcus and related Actinomycetes and their structure analysis. Yakugaku Zasshi 107: 37

    Google Scholar 

  28. Silva CL, Faccioli LH (1988) Tumor necrosis factor (cachectin) mediates induction of cachexia by cord factor from mycobacteria. Infect Immun 56: 3067

    Google Scholar 

  29. Silva CL, Tincani I, Brandao Filho SL, Faccioli LH (1988) Mouse cachexia induced by trehalose dimycolate fromNocardia asteroides. J Gen Microbiol 134: 1629

    Google Scholar 

  30. Silva CL, Faccioli LH, Rocha GM (1988) The role of cachectin/TNF in the pathogenesis of tuberculosis. Braz J Med Biol Res 21: 489

    Google Scholar 

  31. Sumi Y, Kurano S, Kato Y, Sawai H, Tomiyasu I, Kaneda K, Imaizumi S, Yano I (1986) Strain differences in granuloma formation in mice in response to mycolic acid-containing glycolipids in some species ofNocardia andRhodococcus. Jpn J Bacteriol 41: 797

    Google Scholar 

  32. Toubiana R, Ribi E, McLaughlin C, Strain SM (1977) The effect of synthetic and naturally occurring trehalose fatty acid esters in tumor regression. Cancer Immunol Immunother 2: 189

    Google Scholar 

  33. Yamamoto K, Kakimura M, Kato K, Okuyama H, Azuma I (1980) Relationship of anti-tuberculous protection to lung granuloma produced by intravenous injection of synthetic 6-O-mycoloyl-N-acetylmuramyl-l-alanyl-d-isoglutamine with or without specific antigens. Immunology 40: 557

    Google Scholar 

  34. Yano I, Tamiyasu I, Kitabatake S, Kaneda K (1984) Granuloma forming activity of mycolic acid-containing glycolipids inNocardia and related taxa. Acta Leprol (Genève) 2: 341

    Google Scholar 

  35. Yano I, Tomiyasu I, Kaneda K, Kato Y, Sumi Y, Kurano S, Sugimoto N, Sawai H (1987) Isolation of mycolic acid-containing glycolipids inNocardia rubra and their granuloma forming activity in mice. J Pharmacobiodyn 10: 113

    Google Scholar 

  36. Yano I (1988) Structure analysis and granulomagenic activities of mycolic acid-containing glycolipids in acid-fast bacteria. Kekkaku 63: 191

    Google Scholar 

  37. Yano I, Oka S, Natsuhara Y, Kato Y, Tomiyasu I, Kaneda K (1988) Molecular structure and immunopharmacological activities of the new glycolipids containing mycolic acids in Actinomycetales. In: Biology of Actinomycetes '88. Japan Scientific Societies Press, Tokyo, p 469

    Google Scholar 

  38. Yarkoni E, Wang L, Bekierkunst A (1974) Suppression of growth of Ehrlich ascites tumor cells in mice by trehalose-6,6′-dimycolate (cord factor) and BCG. Infect Immun 9: 977

    Google Scholar 

  39. Yarkoni E, Meltzer MS, Rapp HJ (1977) Tumor regression after intralesional injection of emulsified trehalose-6,6′-dimycolate (cord factor); efficacy increases with oil concentration. Int J Cancer 19: 818

    Google Scholar 

  40. Yarkoni E, Rapp HJ, Polonsky J, Lederer E (1978) Immunotherapy with an intralesionally administered synthetic cord factor analogue. Int J Cancer 22: 564

    Google Scholar 

  41. Yarkoni E, Goren MB, Rapp HJ (1979) Effect of sulfolipid I on trehalose-6,6′-dimycolate (cord factor) toxicity and antitumor activity. Infect Immun 24: 586

    Google Scholar 

  42. Yarkoni E, Lederer E, Rapp HJ (1981) Immunotherapy of experimental cancer with a mixture of synthetic muramyl dipeptide and trehalose dimycolate. Infect Immun 32: 273

    Google Scholar 

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Authors and Affiliations

  1. Department of Bacteriology, Osaka City University Medical School, 1-4-54, Asahi-machi, Abeno-ku, 545, Osaka, Japan

    Yayoi Natsuhara, Shiro Oka & Ikuya Yano

  2. Department of Anatomy, Faculty of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113, Tokyo, Japan

    Kenji Kaneda

  3. Osaka Research Institute, Sawai Pharmaceutical Co., Ltd., Ikue 1-8-14, Asahi-ku, 535, Osaka, Japan

    Yayoi Natsuhara & Yoshiko Kato

Authors
  1. Yayoi Natsuhara
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  2. Shiro Oka
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  4. Yoshiko Kato
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  5. Ikuya Yano
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Natsuhara, Y., Oka, S., Kaneda, K. et al. Parallel antitumor, granuloma-forming and tumor-necrosis-factor-priming activities of mycoloyl glycolipids fromNocardia rubra that differ in carbohydrate moiety: Structure—activity relationships. Cancer Immunol Immunother 31, 99–106 (1990). https://doi.org/10.1007/BF01742373

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