Bovine Lactoferrin and LactoferricinTM Inhibit Tumor Metastasis in Mice

  • Yung-Choon Yoo
  • Shikiko Watanabe
  • Ryosuke Watanabe
  • Katsusuke Hata
  • Kei-ichi Shimazaki
  • Ichiro Azuma
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 443)


The effect of a bovine milk protein, lactoferrin (bLf), and a pepsin-generated peptide of bLf, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, was examined in experimental and spontaneous metastasis models using syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-bLf) and Lfcin-B 1 day after tumor inoculation significantly inhibited liver and spleen metastasis of L5178Y-ML25 cells and lung metastasis of B16-BL6 cells, whereas human apo-lactoferrin (apo-hLf) and bovine holo-lactoferrin (holo-Lf) at the dose of 1 mg/mouse did not. Furthermore, both apobLf and Lfcin-B, but not apo-hLf and holo-bLf, inhibited the number of tumor-induced blood vessels and suppressed tumor growth on day 8 after tumor inoculations in an in vivo model. However, in a long-term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo-bLf significantly suppressed the growth of B 16-BL6 cells throughout the examination period, but Lfcin-B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis model, multiple administration of both apo-bLf and Lfcin-B significantly inhibited lung metastasis of B16-BL6 cells, however it was only apo-bLf that exhibited the inhibitory effect of tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. The results suggest that apo-bLf and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of bLf on tumor metastasis maybe related to the property of iron (Fe3+)-saturation.


Lung Metastasis Tumor Metastasis Suppress Tumor Growth Tumor Inoculation Antimetastatic Effect 
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. 1.
    Reiter. B. In “ Development in Dairy Chemistry-3, Lactose and Minor Constituents, ed. P.F. Fox, London, pp. 281–336 (1985). Elsevier Applied Sci. Pub.Google Scholar
  2. 2.
    Masson, P. L., Heremans, J. F. and Schonne, E, J. Exp. Med., 130, 643–658 (1969).PubMedCrossRefGoogle Scholar
  3. 3.
    Hauer, J., Voetsh, W. and Anderer, F.A. Immunol. Lett., 42, 7–12 (1994).PubMedCrossRefGoogle Scholar
  4. 4.
    Arnold, R. R., Brewer, M. and Cauthier, J. J. Infect. Immun., 28, 893–898 (1980).PubMedGoogle Scholar
  5. 5.
    He, J. and Furmanski, P. Nature, 373, 721–724 (1995).PubMedCrossRefGoogle Scholar
  6. 6.
    Lomita, M.. Bellamy, W., Takase, M., Yamauchi, K. Wakabayashi, H. and Kawase, K. J. Dairy Sei., 74, 4137-ßl42(1992).Google Scholar
  7. 7.
    Bellamy, W., Takase, M.. Yamauchi, K., Wakabayashi, H., Kwase, K. and Tomita, M. Biochim. Biophys. Acta, 1121, 134–136 (1992).Google Scholar
  8. 8.
    Bezault. J., Bhimani, R., Wiprovnick, J. and Furmanski, P. Cancer Res., 54, 2310–2312 (1994).Google Scholar
  9. 9.
    Pierce, A., Colavizza, D., Benaissa, M., Macs, P., Tartar, A., Montreuil, J. and Spik, G. Fur. J. Biochem., 196, 177 184 (1991).Google Scholar
  10. 10.
    Shan, H., Kim, A. and Golub, H. J. Leukocyte Biol., 51, 343–349 (1992).Google Scholar
  11. 11.
    Yoo, Y. C., Saiki, I.. Sato, K. and Azuma, 1. Vaccine, 12, 175–180 (1994).Google Scholar
  12. 12.
    Law, B. A. and Reiter. B..1. Dairy Res., 44, 595–599 (1977).CrossRefGoogle Scholar
  13. 13.
    Shimazaki. K., Kawano, N. and Yoo, Y. C. Comp. Biochem. Physiol., 98, 417–422 (1991).Google Scholar
  14. 14.
    Yoo. Y. C.. Saiki. I., Sato, K. and Azuma, I. Vaccine, 10, 792–797 (1992).Google Scholar
  15. 15.
    Saiki, I., Sato, K., Yoo, Y. C., Murata, J., Yoncda, J., Kiso, M.. Hasegawa, M. and Azuma, 1. Int..1. Cancer, 51, 641–045 (1992).Google Scholar
  16. 16.
    Weinberg, E. D. Iron depletion: Life Sci., 50, 1289–1297 (1992).CrossRefGoogle Scholar
  17. 17.
    Anderson, B. F., Baker, I1. M., Norris, G. E., Rice, D. W. and Baker, E. N. J. Mol. Biol., 209. 711–734 (1989).Google Scholar
  18. 18.
    Christenson, B. Fink, J. Merrifield, R. B. and Mauzerall, D. Proc. Natl. Acad. Sci. USA. 85, 5072–5076 (1988)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Yung-Choon Yoo
    • 1
  • Shikiko Watanabe
    • 2
  • Ryosuke Watanabe
    • 1
  • Katsusuke Hata
    • 1
  • Kei-ichi Shimazaki
    • 2
  • Ichiro Azuma
    • 1
  1. 1.Institute of Immunological ScienceHokkaido UniversitySapporo 060Japan
  2. 2.Department of Dairy Science Faculty of AgricultureHokkaido UniversitySapporo 060Japan

Personalised recommendations