Original articles

Cancer Immunology, Immunotherapy

, Volume 30, Issue 3, pp 151-157

Antimetastatic effect of endogenous tumor necrosis factor induced by the treatment of recombinant interferon γ followed by an analogue (GLA-60) to synthetic lipid A subunit

  • Ikuo SaikiAffiliated withInstitute of Immunological Science, Hokkaido University
  • , Hiroaki MaedaAffiliated withInstitute of Immunological Science, Hokkaido University
  • , Jun MurataAffiliated withInstitute of Immunological Science, Hokkaido University
  • , Nobuchika YamamotoAffiliated withInstitute of Immunological Science, Hokkaido University
  • , Makoto KisoAffiliated withDepartment of Applied Bioorganic Chemistry, Gifu University
  • , Akira HasegawaAffiliated withDepartment of Applied Bioorganic Chemistry, Gifu University
  • , Ichiro AzumaAffiliated withInstitute of Immunological Science, Hokkaido University

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Summary

We have investigated the effect of endogenous production of tumor necrosis factor (TNF) induced by the combination of recombinant interferon γ (rIFNγ) as a primer followed by GLA-60 as a trigger (rIFNγ/GLA-60) on murine lung metastases caused by B16-BL6 melanoma. In order to examine the therapeutic effect of endogenous TNF on tumor metastasis, the ability of multiple administrations of rIFNγ/GLA-60 to induce TNF production was also tested. The multiple administrations of rIFNγ/GLA-60 at intervals of 2 days were effective for the induction of endogenous TNF in mice but continuous multiple administrations of them for 2–4 days were not. In tumor-bearing mice, the production of endogenous TNF by rIFNγ/GLA-60 was less than that of normal mice, but treatment 3 days after the surgical excision of primary tumors showed the endogenous TNF production to be similar to that in normal mice. In the experimental lung metastasis model, intravenous administration of rIFNγ followed by intravenous or intranasal administration of GLA-60 showed potent inhibition of lung metastases of B16-BL6 melanoma, whereas the reverse sequence of administration (GLA-60/rIFNγ) or administration of a mixture of rIFNγ and GLA-60, which cannot induce the production of TNF, caused no inhibition of lung metastases. These results indicated that the regression of tumor metastases by rIFNγ/GLA-60 was mediated by the production of endogenous TNF in addition to the direct effects of both immunostimulants. Furthermore, the administration of rIFNγ and GLA-60 significantly inhibited the tumor metastases in spontaneous lung metastasis model. These results may provide a promising approach for the treatment of cancer metastasis as a result of its ability to induce endogenous TNF.