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Enhanced in vivo sensitivity to interferon with in vitro resistant B16 tumor cells in mice

  • Original Articles
  • Melanoma, Antitumor Response, Interferon Resistance, rHulFNαA/D
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Abstract

Mouse B16 melanoma cells rapidly develop resistance to the antiproliferative effects of interferon α (IFNα) and interferon β (IFNβ) when they are exposed to the interferons in vitro. This resistance was characterized to be non-genetic and dose-dependent, and does not alter other IFN-induced effects such as antiviral effects and elevation of 2′,5′-oligoadenylate synthetase activity in IFN-treated cells. The study of these IFN-resistant cells has been extended to an in vivo tumor model. Resistance, if it occurred in vivo, did not adversely affect the survival of IFN-treated mice. Further, IFN-treated mice inoculated with B16 cells that were resistant in vitro (B16αres cells) survived significantly longer than IFN-treated mice inoculated with B16 cells that were sensitive in vitro. The IFN-treated B16αres-inoculated mice had a significantly higher cure rate as well. The prolonged survival of the mice bearing B16αres cell tumors did not seem to be caused by the slower growth rate of the B16αres cells, since experiments performed with a tenfold higher B16αres cell inoculum and a tenfold lower B16 cell inoculum did not show any change in the survival pattern. It is clear that in vitro resistant B16αres cells are more sensitive to antitumor effects induced by IFN in vivo than in vitro sensitive B16 cells.

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References

  1. Belardelli F, Gresser I, Maury C, Maunoury M-T (1982) Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. I. Int J Cancer 30: 813

    PubMed  Google Scholar 

  2. Belardelli F, Gresser I, Maury C, Mounoury M-T (1982) Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. II. Role of host mechanisms. Int J Cancer 30: 821

    PubMed  Google Scholar 

  3. Brunda M, Rosenbaum D, Stern L (1984) Inhibition of experimentally-induced murine metastases by recombinant alpha interferon: correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases. Int J Cancer 34: 421

    PubMed  Google Scholar 

  4. Brunda M, Sulich V, Bellantoni D (1987) The anti-tumor effect of recombinant interferon alpha or gamma is influenced by tumor location. Int J Cancer 40: 807

    PubMed  Google Scholar 

  5. Campbell JB, Grunberger T, Kochman MA, White SL (1975) A microplaque reduction assay for human and mouse interferon. Can J Microbiol 21: 1247

    PubMed  Google Scholar 

  6. Faltynek CR, Princler GL, Schwabe M, Shata MT, Lewis GK, Kamin-Lewis RM (1990) Characterization of the binding of radioiodinated hybrid recombinant IFNαA/D to murine and human lymphoid cell lines. J Interferon Res 10: 55

    PubMed  Google Scholar 

  7. Fidler IJ (1973) Selection of successive tumor lines for metastasis. Nat New Biol 242: 148

    PubMed  Google Scholar 

  8. Fleischmann CM, Fleischmann WR Jr (1991) Resistance to the antiproliferative activity of IFNα: further characterization and demonstration of antagonistic effects of IFNγ. J Biol Regul Homeost Agents 5: 34

    PubMed  Google Scholar 

  9. Fleischmann WR Jr (1982) Potentiation of the direct anticellular activity of mouse interferons: mutual synergism and interferon concentration dependence. Cancer Res 42: 869

    PubMed  Google Scholar 

  10. Fleischmann WR Jr, Fleischmann CM, Gindhart T (1986) Effect of hyperthermia on the antiproliferative activities of murine α, β, and γ-interferons: differential enhancement of murine γ-interferon. Cancer Res 46: 8

    PubMed  Google Scholar 

  11. Fleischmann CM, Fleischmann WR Jr (1988) Differential antiproliferative activities of IFNs α, β, and γ: kinetics of establishment of their antiproliferative effects and the rapid development of resistance to IFNs α and β. J Biol Regul Homeost Agents 2: 173

    PubMed  Google Scholar 

  12. Fleischmann WR Jr, Fleischmann CM (1992) Mechanisms of interferons' antitumor actions. In: Baron S, Coppenhaver D, Dianzani F, et al (eds) Interferon: principles and medical applications. The University of Texas Medical Branch, Galveston, p 299

    Google Scholar 

  13. Fleischmann WR Jr, Koren S, Fleischmann CM (1992) Orally administered interferons exert their white blood cell suppressive effects via a novel mechanism. Proc Soc Exp Biol Med 201: 200

    PubMed  Google Scholar 

  14. Gresser I (1991) Antitumor effects of interferons: past, present and future. Br J Haematol 79 [Suppl 1]: 1

    Google Scholar 

  15. Gresser I, Maury C, Carnaud C, De Mayer E, Maunoury M-T, Belardelli F (1990) Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases. Int J Cancer 46: 468

    PubMed  Google Scholar 

  16. Lee S, Chiu H, Rinderknecht E, Sabo W, Stebbing N (1983) Importance of treatment regimen of interferon as an antitumor agent. Cancer Res 43: 4172

    PubMed  Google Scholar 

  17. Maekawa R, Kitagawa T, Hojo K, Wada T, Sato K (1988) Distinct antitumor mechanisms of recombinant murine interferon-γ against two murine tumor models. J Interferon Res 8: 227

    PubMed  Google Scholar 

  18. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55

    PubMed  Google Scholar 

  19. Nishimura J, Mitsui K, Ishikawa T, et al (1985) Antitumor and antimetastatic activities of human recombinant interferon alpha A/D. Clin Exp Metastasis 3: 295

    PubMed  Google Scholar 

  20. Ramani P, Balkwill F (1989) Action of recombinant alpha interferon against experimental and spontaneous metastases in a murine model. Int J Cancer 43: 140

    PubMed  Google Scholar 

  21. Rehberg E, Kelder B, Hoal EG, Pestka S (1982) Specific molecular activities of recombinant and hybrid leukocyte interferons. J Biol Chem 257: 11497

    PubMed  Google Scholar 

  22. Reid TR, Race ER, Wolff BH, Friedman RM, Merigan TC, Basham TY (1989) Enhanced in vivo therapeutic response to interferon in mice with an in vitro interferon-resistant B-cell lymphoma. Cancer Res 49: 4163

    PubMed  Google Scholar 

  23. Tabata Y, Uno K, Muramatsu S, Ikada Y (1989) In vivo effects of recombinant interferon alpha A/D incorporated in gelatin microspheres on murine tumor cell growth. Jpn J Cancer Res 80: 387

    PubMed  Google Scholar 

  24. Tada H, Shiho O, Kurushima K, Koyama M, Tsukamoto K (1986) An improved colorimetric assay for interleukin 2. J Immunol Methods 93: 157

    PubMed  Google Scholar 

  25. Uno K, Shimizu S, Ido M, et al (1985) Direct and indirect effects of interferon on in vivo murine tumor cell growth. Cancer Res 45: 1320

    PubMed  Google Scholar 

  26. Uno K, Shimizu S, Inaba K, et al (1988) Effect of recombinant human interferon-αA/D on in vivo murine tumor cell growth. Cancer Res 48: 2366

    PubMed  Google Scholar 

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Supported by U. S. Public Health Service grant no. CA50752 awarded by the National Cancer Institute, Department of Health and Human Services (W. R. F.) and by a James W. McLaughlin Fellowship (C. M. F.)

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Fleischmann, C.M., Stanton, G.J. & Fleischmann, W.R. Enhanced in vivo sensitivity to interferon with in vitro resistant B16 tumor cells in mice. Cancer Immunol Immunother 39, 148–154 (1994). https://doi.org/10.1007/BF01533379

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  • DOI: https://doi.org/10.1007/BF01533379

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