Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Experimental screening of two BCG preparations produced according to different principles

Immunostimulating properties, safety, and antitumor activity

  • 22 Accesses

  • 10 Citations

Summary

Two BCG preparations produced according to different principles for use as an adjunct to surgery in a comparative clinical trial in melanoma patients have been examined for immunostimulating, toxic, and antitumor activity in various murine and guinea pig models and for immunostimulation in vitro of human lymphocytes. One BCG preparation was prepared in the classic way, i.e., grown as a surface culture and subsequently homogenized in a ball mill, while the other preparation was grown as a dispersed culture.

In general, a comparable effect on spleen weight of the proliferation of lymph node cells and activation of spleen macrophages was observed when a similar amount of culturable particles of either BCG preparation were administered. In parallel with these effects, an increase of the serum glutamic pyruvic transaminase was detected. Activation of natural killer cells and the induction of an immune reaction in lymph nodes appeared to be a function of the total amount of injected viable and dead micro-organisms.

The synergistic effect of the BCG preparation grown as a dispersed culture on the stimulation of human lymphocytes by phytohaemagglutinin, lacking in the BCG preparation grown as surface culture and subsequently homogenized in a ball mill, was due to the stabilizers present in the former material.

The effect of BCG treatment on the growth of an originally chemically induced murine fibrosarcoma depended on the treatment schedule. Growth enhancement, growth retardation, or no effect was observed, depending on the regimen used. Although differences between the two BCG preparations could be demonstrated in the various models the clinical relevance of these reported results can only be evaluated in conjunction with the outcome of the comparative clinical trial.

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

References

  1. 1.

    Bartlett GL, Zbar B, Rapp HJ (1972) Suppression of murine tumor growth by immune reaction to the Bacillus Calmette-Guérin strain of Mycobacter bovis. J Natl Cancer Inst 48:245

  2. 2.

    Bergmeier HU (1974) Methoden der enzymatischen Analysen. Verlag Chemie, Weinheim

  3. 3.

    Bonta IL, Noordhoek J (1973) Anti-inflammatory mechanism of inflammed tissue factor. Agents Actions 3:348

  4. 4.

    Bruynzeel DP, Ettekoven H, Kreeftenberg JG (1978a) The synergistic activity of BCG on the stimulation of lymphocytes with Concanavalin A and lipopolysaccharide. Cancer Immunol Immunother 3:253

  5. 5.

    Bruynzeel DP, Ettekoven H, Kreeftenberg JG (1978b) Proposals for quality control methods of bacterial vaccines for immunostimulation. II. In vivo and in vitro stimulation of lymphocytes by BCG. Dev Biol Stand 38:91

  6. 6.

    Carter SK (1976) Immunotherapy of cancer in man: Current status and prospectus. Ann NY Acad Sci 277:722

  7. 7.

    Chassoux D, Salomon JC (1975) Therapeutic effect of intratumoral injection of BCG and other substances in rats and mice. Int J Cancer 16:515

  8. 8.

    Creau-Goldberg N, Salomon JC (1980) Immunotherapy of primary methylcholanthrene-induced mouse tumors by intratumoral BCG. Br J Cancer 41:541

  9. 9.

    Georghiu M, Chambon L, Serie C, Juvin-Calmette D (1978) Immuno-BCG Pasteur F vaccine. Dev Biol Stand 38:29

  10. 10.

    Hemert PA van (1973) Vaccine production as a unit process. Thesis, Delft

  11. 11.

    Hemert PA van, Tiesjema RH (1977) Possible use of the oxygen uptake rate in the evaluation of BCG vaccines. J Biol Stand 5:121

  12. 12.

    Hopper DG, Pimm MV, Baldwin RW (1976) Silica abrogation of mycobacterial adjuvant contact suppression of tumor growth in rats and athymic mice. Cancer Immunol Immunother 1:143

  13. 13.

    Hortobagyi GH, Richman SP, Dandridge K, Gutterman JU, Blumenschein GR, Hersch EM (1978) Immunotherapy with BCG administered by scarification. Standardization of reactions and management of side effects. Cancer 42:2293

  14. 14.

    Jong WH de, Steerenberg PA, Ursem PS, Osterhaus ADME, Vos JG, Ruitenberg EJ (1980) The athymic rat. III. Natural cell-mediated cytotoxicity. Clin Immunol Immunopathol 17:163

  15. 15.

    Jurczyk-Procyk S, Martin M, Dobouch P, Gheorgiu M, Economides F, Khalil A, Rappaport H (1976) Toxicity studies of intravenously administered BCG in baboons. Cancer Immunol Immunother 1:55

  16. 16.

    Kreider JW, Bartlett GL, Purnell DM (1976) Suitability of rat mammary adenocarcinoma 13762 as a model for BCG immunotherapy. J Natl Cancer Inst 56:797

  17. 17.

    LaGrange PH, Gheorghiu M (to be published in Cancer Immunol and Immunother) Anti-tumoral activity of two BCG vaccine preparations against the Lewis lung carcinoma in mice.

  18. 18.

    Likhite VV (1976) Experimental cancer immunotherapy: comparison of tumor rejection in F344 rats given live Mycobacterium bovis (strain BCG) and killed Corynebacterium parvum. J Natl Cancer Inst 56:985

  19. 19.

    Mackaness GB, Auclair DJ, LaGrange PH (1973) Immunopotentiation with BCG. I. Immune response to different strains and preparations. J Natl Cancer Inst 51:1655

  20. 20.

    Mathé G (1978) Systemic active immunotherapy is shifting from the Middle Ages to a Renaissance period. I. The multiplication of randomized trials showing significant effect of active immunotherapy on residual minimal disease. Cancer Immunol Immunother 5:149

  21. 21.

    Pierce CH, Dubos RJ, Schaefer WB (1956) Differential characteristics in vitro and in vivo of several substrains of BCG. American Review of Tuberculosis 74:681

  22. 22.

    Pittman M, Cox CB (1965) Pertussis vaccine testing for freedom-from-toxicity. Appl Microbiol 13:447

  23. 23.

    Portelance V, Quevillon M, Page Y (1976) Toxic effect of massive doses of BCG in mice, guinea pigs and monkeys. Cancer Immunol Immunother 1:63

  24. 24.

    Potter MR, Moore M (1980) The effect of BCG stimulation on natural cytotoxicity in the rat. Immunology 39:427

  25. 25.

    Ruitenberg EJ, Noorle Jansen LM van, Kruizinga W, Steererberg PA (1976) Effect of pretreatment with Bacillus Calmette-Guérin on the course of a Listeria monocytogenes infection in normal and congenitally athymic (nude) mice. Br J Exp Pathol 57:310

  26. 26.

    Ruitenberg EJ, Steerenberg PA, Norrle Jansen LM van (1978) Proposals for quality control methods of bacterial vaccines for immunostimulation. III. Effect of BCG and C. parvum on in vivo Listeria clearance and tumor growth. Dev Biol Stand 38:97

  27. 27.

    Schwarzenberg L, Simmler MC, Pico JL (1976) Human toxicology of BCG applied in cancer immunotherapy. Cancer Immunol Immunother 1:69

  28. 28.

    Sekhuis VM, Bleiker MA, Sirks JL, Cohen H (1974) Comparison of two types of freeze-dried BCG vaccine products. II. Results of vaccination of man. J Biol Stand 2:169

  29. 29.

    Sirks JL, Cohen H, Smith L (1971) Production of freeze-dried BCG vaccine. Symposium Series in Immunobiological Standardization 17:163

  30. 30.

    Sirks JL, Ruitenberg EJ (1978) Proposals for quality control methods of bacterial vaccines for immunostimulation. I. General considerations. Dev Biol Stand 38:87

  31. 31.

    Sparks FC, Breeding JH (1974) Tumor regression and enhancement resulting from immune therapy with Bacillus Calmette Guérin and neuraminidase. Cancer Res 34:3262

  32. 32.

    Tokunaga T, Kataoka T, Nakamura RM, Yamamoto S, Takana T (1973) Tumor immunity induced by BCG tumor cell mixtures in syngeneic mice. Jpn J Med Sci Biol 26:71

  33. 33.

    Tracey DE, Wolfe SA, Durdik JM, Henney CS (1977) BCG-induced murine effector cells. I. Cytolytic activity in peritoneal exudates: An early response to BCG. J Immunol 119:1145

  34. 34.

    Woodruff MFA (1979) Current state of clinical immunotherapy. Transplant Proc 11:1077

Download references

Author information

Correspondence to J. G. Kreeftenberg.

Additional information

Now Fellow of the Koningin Wilhelmina Fonds of the National Cancer League of The Nederlands

Now Secretary of the Health Council, The Hague, The Netherlands

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kreeftenberg, J.G., de Jong, W.H., Ettekoven, H. et al. Experimental screening of two BCG preparations produced according to different principles. Cancer Immunol Immunother 12, 21–29 (1981). https://doi.org/10.1007/BF00200308

Download citation

Keywords

  • Melanoma
  • Natural Killer Cell
  • Ball Mill
  • Human Lymphocyte
  • Fibrosarcoma