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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1996 Mar;103(3):499–505. doi: 10.1111/j.1365-2249.1996.tb08308.x

Effect of in vivo activation of natural killer (NK) cells by a tilorone analogue on the survival of mice injected intravenously with different experimental murine tumours

I ALGARRA *, A GONZÁLEZ *, M PÉREZ *, J J GAFORIO *, F GARRIDO *
PMCID: PMC2200376  PMID: 8608652

Abstract

We studied the effect of a tilorone analogue (RMI 10,874DA) and anti-asialo GM1 serum on the survival of BALB/c and C57B1/6 mice after i.v. injections of different syngeneic murine tumour cells. Tumour lines used were different clones from chemically (GR9 wild type, GR9.B9, B7.1.B4, B7.1.B5, B7.2.38), and ultraviolet light (GRUV3)-induced sarcomas; B16 melanoma and LSTRA and YC8 lymphomas. Pretreatment of mice with tilorone inhibited metastatic colonization and increased survival significantly in all cases. In some tumour systems, the effect was attenuated when high numbers of cells were injected. Abrogation of NK cells with anti-asialo GM1 serum significantly decreased (in all tumours and at different cell doses) survival in comparison with untreated mice injected with tumours, regardless of cell dose used. These results clearly suggest that NK cell activation in vivo by the tilorone analogue we tested prolongs survival and inhibits metastasis formation in mice, even when pretreatment consists of a single dose of the analogue.

Keywords: H-2 antigens, metastases, natural killer cells, survival, therapy

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References

  • 1.Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980;283:139–45. doi: 10.1038/283139a0. [DOI] [PubMed] [Google Scholar]
  • 2.Nicolson GL. Cancer metastasis; organ colonization and the cell-surface properties of malignant cells. Biochem Biophys Acta. 1982;695:113–73. doi: 10.1016/0304-419x(82)90020-8. [DOI] [PubMed] [Google Scholar]
  • 3.Schirrmacher V. Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies. Adv Cancer Res. 1985;43:1–71. doi: 10.1016/s0065-230x(08)60942-2. [DOI] [PubMed] [Google Scholar]
  • 4.Hanna N. In vivo activities of NK cells against primary and metastatic tumors in experimental animals. In: Lotzova E, Herbermman RB, editors. Inmunulogy of natural killer cells. Vol. 2. Boca Raton: CRC Press; 1987. pp. 1–10. Vol. 2. [Google Scholar]
  • 5.Aboud M, Kingsmore S, Segal S. Role of natural killer cells in controlling local tumor formation and metastatic manifestation of different 3ll Lewis lung carcinoma cell clones. Nat Inmun. 1993;12:17–24. [PubMed] [Google Scholar]
  • 6.Pross HF. The involment of natural killer cells in human malignant disease. In: Lotzova E, Herberman RB, editors. Inmunology of natural killer cells. Vol. 2. Boca Raton: CRC Press; 1987. pp. 11–29. Vol. 2. [Google Scholar]
  • 7.Fisch P, Malkovsky M, Braakman E, et al. Gamma/delta T cell clones and natural killer cell clones mediate distinct pattern of non-major histocompatibility complex-restricted cytolysis. J Exp Med. 1990;171:1567–79. doi: 10.1084/jem.171.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Ljunggren HG, Kärre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today. 1990;11:237–44. doi: 10.1016/0167-5699(90)90097-s. [DOI] [PubMed] [Google Scholar]
  • 9.Bezouska K, Yuen CT, O'Brien J, et al. Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity. Nature. 1994;372:150–7. doi: 10.1038/372150a0. [DOI] [PubMed] [Google Scholar]
  • 10.Herberman RB, Holten HT. Natural killer cells as antitumor effector cells. J Natl Cancer Inst. 1979;62:441–5. doi: 10.1093/jnci/62.3.441. [DOI] [PubMed] [Google Scholar]
  • 11.Gorelik E, Wiltrout RH, Okumura K, Habu S, Heberman RB. Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J Cancer. 1982;30:107–13. doi: 10.1002/ijc.2910300118. [DOI] [PubMed] [Google Scholar]
  • 12.Papa MZ, Mule JJ, Rosenberg SA. Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three distinct histological types. Cancer Res. 1986;46:4973–8. [PubMed] [Google Scholar]
  • 13.Toshitani A, Taniguchi K, Kawano Y, Nomoto K. Inverse relationship in H-2 associated lysis between NK cells and rIL-2 activated killer cells: evidence from in vitro killing and metastatic experiments. Cell Immunol. 1987;108:188–202. doi: 10.1016/0008-8749(87)90203-6. [DOI] [PubMed] [Google Scholar]
  • 14.Naume B, Gately M, Espevik T. A comparative study of IL-12 (cytotoxic lymphocyte maturation factor)-, IL-2-, and IL-7-induced effects on inmunomagnetically purified CD56+ NK cells. J Immunol. 1992;148:2429–34. [PubMed] [Google Scholar]
  • 15.Humphries MJ, Matsumoto K, White SL, Molyneux RJ, Olden K. Augmentation of murine natural killer cell activity by swainsonine, a new antimetastatic immunomodulator. Cancer Res. 1988;48:1410–5. [PubMed] [Google Scholar]
  • 16.Nakatsuka M, Kumazawa Y, Homma JY, Kiso M, Hasegawa A. Inhibition in mice of experimental metastasis of B16 melanoma by the synthetic lipid A-subunit analogue GLA-60. Int J Immunopharmacol. 1991;13:11–19. doi: 10.1016/0192-0561(91)90020-8. [DOI] [PubMed] [Google Scholar]
  • 17.Gidlund M, Örn A, Wigzell H, Senik A, Gresser I. Enhanced NK cell activity in mice injected with interferon and interferon inducers. Nature. 1978;273:759–61. doi: 10.1038/273759a0. [DOI] [PubMed] [Google Scholar]
  • 18.Mayer GD, Krueger RF. Tilorone hydrochloride: mode of action. Science. 1970;169:1214–5. doi: 10.1126/science.169.3951.1214. [DOI] [PubMed] [Google Scholar]
  • 19.Krueger RF, Mayer GD. Tilorone hidrochloride: an orally active antiviral agent. Science. 1970;169:1213–4. doi: 10.1126/science.169.3951.1213. [DOI] [PubMed] [Google Scholar]
  • 20.Mayer GD, Krueger RF. Tilorone hidrochloride: a new antiviral agent and interferon inducer. In: Stringfellow DA, editor. Interferon and interferon inducers. New York/Basel: M. Dekker; 1984. pp. 97–120. Clinical aplications. [Google Scholar]
  • 21.Welsh RM. Natural killer cells and interferon. Crit Rev Immunol. 1984;5:55–89. [PubMed] [Google Scholar]
  • 22.Adamson RH. Antitumor activity of tilorone hydrochloride against some rodent tumors: preliminary report. J Nat Cancer Inst. 1971;46:431–8. [PubMed] [Google Scholar]
  • 23.Albrecht WL. Tilorone and analogs: physicochemical and antiviral properties. In: Chirigos MA, editor. Modulation of host immune resistance in the prevention or treatment of induced neoplasm. Washington, DC: US Government printing office; 1977. [Google Scholar]
  • 24.Munson AE, Munson JA, Regelson W, Wampler GL. Effect of tilorone hydrochloride and congeners on reticuloendothelial systems. Tumor and immune response. Cancer Res. 1972;32:1397–403. [PubMed] [Google Scholar]
  • 25.Wampler GL, Munson AE, Regelson W. Tilorone and congeners: new antitumor agents with stimulating effects on host defense mechanism. Proc Am Assoc Cancer Res. 1972;13:120–2. [Google Scholar]
  • 26.Wampler GL, Regelson W. Antitumor activity of tilorone and congeners in murine screening tumor systems. In: Chirigos MA, editor. Modulation of host immune resistance in the prevention or treatment of induced neoplasm. Washington, DC: US Goverment printing office; 1977. [Google Scholar]
  • 27.Algarra I, Pérez M, Höglund P, Gaforio JJ, Ljunggren HG, Garrido F. Generation and control of metastasis in experimental tumor systems; inhibition of experimetal metastases by a tilorone analogue. Int J Cancer. 1993;54:518–23. doi: 10.1002/ijc.2910540327. [DOI] [PubMed] [Google Scholar]
  • 28.Algarra I, Pérez M, Gaforio JJ, Gasca F, Garrido F. In vivo activation of NK cells induces inhibition of lung colonization of H-2 positive and H-2 negative fibrosarcoma tumor clones. Clin Exp Metastasis. 1994;13:31–36. doi: 10.1007/BF01784331. [DOI] [PubMed] [Google Scholar]
  • 29.Pérez M, Garrido A, Algarra I, Garrido F. Different H-2 phenotypes in clones derived from a new BALB/c solid tumor. Its relevance for local tumor growth. Immunología. 1985;4:60–69. [Google Scholar]
  • 30.Garrido A, Pérez M, Delgado C, Garrido ML, Rojano J, Algarra I, Garrido F. Influence of class I H-2 gene expression on local tumor growth. Exp Clin Immunogenet. 1986;13:98–110. [PubMed] [Google Scholar]
  • 31.Algarra I, Öhlen C, Pérez M, Ljunggren HG, Klein G, Garrido F, Kärre K. NK sensitivity and lung clearance of MHC class I deficient cells within a heterogeneous fibrosarcoma. Int J Cancer. 1989;44:675–80. doi: 10.1002/ijc.2910440420. [DOI] [PubMed] [Google Scholar]
  • 32.Pérez M, Algarra I, Ljunggren HG, et al. A weakly tumorigenic phenotype with high MHC class I expression is associated with high metastatic potential after surgical removal of the primary murine fibrosarcoma. Int J Cancer. 1990;46:258–61. doi: 10.1002/ijc.2910460219. [DOI] [PubMed] [Google Scholar]
  • 33.Gaforio JJ, Perez M, Algarra I, Mialdea MJ, Ljunggren HG, Garrido F. Differential mRNA levels of c-myc, c-fos and MHC class I in several clones of a murine fibrosarcoma. Int J Cancer. 1991;49:1–5. doi: 10.1002/ijc.2910490618. [DOI] [PubMed] [Google Scholar]
  • 34.Algarra I, Gaforio JJ, Garrido A, Mialdea MJ, Perez M, Garrido F. Heterogeneity of MHC-class I antigens in clones of methylcholan-threne induced tumors. Implications for local growth and metastasis. Int J Cancer. 1991;6(Suppl.):73–81. doi: 10.1002/ijc.2910470716. [DOI] [PubMed] [Google Scholar]
  • 35.Young IT. Proof without prejudice: use of the Kolmogorov-Smirnov test for analysis of histograms from flow systems and other sources. J Histochem Cytochem. 1977;25:935–42. doi: 10.1177/25.7.894009. [DOI] [PubMed] [Google Scholar]
  • 36.Goldstein M, Laszlo J. Interferon therapy in cancer: from imaginom to interferon. Cancer Res. 1986;46:4315–29. [PubMed] [Google Scholar]

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