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. 1993 Mar;67(3):447–455. doi: 10.1038/bjc.1993.86

Tumour growth inhibition in mice by glycosylated recombinant human lymphotoxin: analysis of tumour-regional mononuclear cells involved with its action.

I Funahashi 1, H Watanabe 1, T Abo 1, K Indo 1, H Miyaji 1
PMCID: PMC1968267  PMID: 8439496

Abstract

We compared the antitumour effects of glycosylated LT (gLT), nonglycosylated LT and TNF against a solid tumour in mice. We found that: (a) The systemic administration of gLT showed significant antitumour activity. These effects were, however, quite small in nude mice. Nonglycosylated LT and TNF attained the same degree of effectiveness as gLT, but at a 5-times higher dose. The serum half-life of gLT was 3-fold longer than that of nonglycosylated LT and 22-fold longer than that of TNF. (b) The effect of gLT was significantly blocked by pretreatment with anti-asialo GM1 antibody. Treatment with gLT produced a significant reduction in numbers of tumour-regional mononuclear cells, which in turn, produced increases intensive necrosis. (c) Mononuclear cells in the tumour tissues before gLT-injection were predominantly IL-2 receptor +/CD3- cells and CD3+ cells. Pretreatment with the anti-asialo GM1 antibody produced a drastic reduction of IL-2 receptor +/CD3- cells. These findings suggest that the efficient antitumour effect of gLT is due to a longer serum half-life than that of nonglycosylated LT or TNF in vivo, and its function is largely mediated by IL-2 receptor +/CD3- cells.

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Selected References

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  1. Abo T., Ohteki T., Seki S., Koyamada N., Yoshikai Y., Masuda T., Rikiishi H., Kumagai K. The appearance of T cells bearing self-reactive T cell receptor in the livers of mice injected with bacteria. J Exp Med. 1991 Aug 1;174(2):417–424. doi: 10.1084/jem.174.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aggarwal B. B., Eessalu T. E., Hass P. E. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19;318(6047):665–667. doi: 10.1038/318665a0. [DOI] [PubMed] [Google Scholar]
  3. Aggarwal B. B., Henzel W. J., Moffat B., Kohr W. J., Harkins R. N. Primary structure of human lymphotoxin derived from 1788 lymphoblastoid cell line. J Biol Chem. 1985 Feb 25;260(4):2334–2344. [PubMed] [Google Scholar]
  4. Aggarwal B. B., Moffat B., Harkins R. N. Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. J Biol Chem. 1984 Jan 10;259(1):686–691. [PubMed] [Google Scholar]
  5. Andrews J. S., Berger A. E., Ware C. F. Characterization of the receptor for tumor necrosis factor (TNF) and lymphotoxin (LT) on human T lymphocytes. TNF and LT differ in their receptor binding properties and the induction of MHC class I proteins on a human CD4+ T cell hybridoma. J Immunol. 1990 Apr 1;144(7):2582–2591. [PubMed] [Google Scholar]
  6. Asher A., Mulé J. J., Reichert C. M., Shiloni E., Rosenberg S. A. Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo. J Immunol. 1987 Feb 1;138(3):963–974. [PubMed] [Google Scholar]
  7. Beran M., Andersson B. S., Kelleher P., Whalen K., McCredie K., Gutterman J. Diversity of the effect of recombinant tumor necrosis factors alpha and beta on human myelogenous leukemia cell lines. Blood. 1987 Mar;69(3):721–726. [PubMed] [Google Scholar]
  8. Broudy V. C., Harlan J. M., Adamson J. W. Disparate effects of tumor necrosis factor-alpha/cachectin and tumor necrosis factor-beta/lymphotoxin on hematopoietic growth factor production and neutrophil adhesion molecule expression by cultured human endothelial cells. J Immunol. 1987 Jun 15;138(12):4298–4302. [PubMed] [Google Scholar]
  9. Crossland K. D., Lee V. K., Chen W., Riddell S. R., Greenberg P. D., Cheever M. A. T cells from tumor-immune mice nonspecifically expanded in vitro with anti-CD3 plus IL-2 retain specific function in vitro and can eradicate disseminated leukemia in vivo. J Immunol. 1991 Jun 15;146(12):4414–4420. [PubMed] [Google Scholar]
  10. Cuturi M. C., Murphy M., Costa-Giomi M. P., Weinmann R., Perussia B., Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. doi: 10.1084/jem.165.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dumonde D. C., Wolstencroft R. A., Panayi G. S., Matthew M., Morley J., Howson W. T. "Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation. Nature. 1969 Oct 4;224(5214):38–42. doi: 10.1038/224038a0. [DOI] [PubMed] [Google Scholar]
  12. Evans C. H., Heinbaugh J. A. Lymphotoxin cytotoxicity, a combination of cytolytic and cytostatic cellular responses. Immunopharmacology. 1981 Dec;3(4):347–359. doi: 10.1016/0162-3109(81)90027-8. [DOI] [PubMed] [Google Scholar]
  13. Funahashi I., Kawatsu M., Kajikawa T., Takeo K., Asahi T., Kakutani T., Yamashita T., Kawaharada H., Watanabe K. Usefulness of glycosylated recombinant human lymphotoxin for growth inhibition of human and murine solid tumors and experimental metastasis in mice. J Immunother (1991) 1991 Feb;10(1):28–38. doi: 10.1097/00002371-199102000-00005. [DOI] [PubMed] [Google Scholar]
  14. Garbrecht F. C., Russo C., Weksler M. E. Long-term growth of human T cell lines and clones on anti-CD3 antibody-treated tissue culture plates. J Immunol Methods. 1988 Feb 24;107(1):137–142. doi: 10.1016/0022-1759(88)90019-1. [DOI] [PubMed] [Google Scholar]
  15. Granger G. A., Kolb W. P. Lymphocyte in vitro cytotoxicity: mechanisms of immune and non-immune small lymphocyte mediated target L cell destruction. J Immunol. 1968 Jul;101(1):111–120. [PubMed] [Google Scholar]
  16. Gray P. W., Aggarwal B. B., Benton C. V., Bringman T. S., Henzel W. J., Jarrett J. A., Leung D. W., Moffat B., Ng P., Svedersky L. P. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature. 1984 Dec 20;312(5996):721–724. doi: 10.1038/312721a0. [DOI] [PubMed] [Google Scholar]
  17. Inagawa H., Oshima H., Soma G., Mizuno D. TNF induces endogenous TNF in vivo: the basis of EET therapy as a combination of rTNF together with endogenous TNF. J Biol Response Mod. 1988 Dec;7(6):596–607. [PubMed] [Google Scholar]
  18. Kawatsu M., Funahashi I., Kajikawa T., Takeo K., Asahi T., Yamashita T., Kawaharada H., Watanabe K. Synergistic antitumor effect of glycosylated recombinant human lymphotoxin with human interferon-gamma on lymphotoxin-sensitive human tumor. J Interferon Res. 1990 Oct;10(5):519–529. doi: 10.1089/jir.1990.10.519. [DOI] [PubMed] [Google Scholar]
  19. Kawatsu M., Takeo K., Kajikawa T., Funahashi I., Asahi T., Kakutani T., Yamashita T., Kawaharada H., Watanabe K. The pharmacokinetic pattern of glycosylated human recombinant lymphotoxin (LT) in rats after intravenous administration. J Pharmacobiodyn. 1990 Sep;13(9):549–557. doi: 10.1248/bpb1978.13.549. [DOI] [PubMed] [Google Scholar]
  20. Kern D. E., Peace D. J., Klarnet J. P., Cheever M. A., Greenberg P. D. Il-4 is an endogenous T cell growth factor during the immune response to a syngeneic retrovirus-induced tumor. J Immunol. 1988 Oct 15;141(8):2824–2830. [PubMed] [Google Scholar]
  21. Khan A., Martin E. S., Webb K., Weldon D., Hill N. O., Duvall J., Hill J. M. Regression of malignant melanoma in a dog by local injections of a partially purified preparation containing human alpha-lymphotoxin. Proc Soc Exp Biol Med. 1982 Feb;169(2):291–294. doi: 10.3181/00379727-169-41345. [DOI] [PubMed] [Google Scholar]
  22. Locksley R. M., Heinzel F. P., Shepard H. M., Agosti J., Eessalu T. E., Aggarwal B. B., Harlan J. M. Tumor necrosis factors alpha and beta differ in their capacities to generate interleukin 1 release from human endothelial cells. J Immunol. 1987 Sep 15;139(6):1891–1895. [PubMed] [Google Scholar]
  23. Londei M., Grubeck-Loebenstein B., de Berardinis P., Greenall C., Feldmann M. Efficient propagation and cloning of human T cells in the absence of antigen by means of OKT3, interleukin 2, and antigen-presenting cells. Scand J Immunol. 1988 Jan;27(1):35–46. doi: 10.1111/j.1365-3083.1988.tb02321.x. [DOI] [PubMed] [Google Scholar]
  24. Manda T., Shimomura K., Mukumoto S., Kobayashi K., Mizota T., Hirai O., Matsumoto S., Oku T., Nishigaki F., Mori J. Recombinant human tumor necrosis factor-alpha: evidence of an indirect mode of antitumor activity. Cancer Res. 1987 Jul 15;47(14):3707–3711. [PubMed] [Google Scholar]
  25. Mikami T., Kurisu K., Kiya K., Mukada K., Kawamoto K., Hotta T., Uozumi T. Antitumor effect of recombinant human lymphotoxin on a tumor line of human malignant glioma. Hiroshima J Med Sci. 1989 Sep;38(3):103–107. [PubMed] [Google Scholar]
  26. Murphy M., Perussia B., Trinchieri G. Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hematopoietic precursor cells. Exp Hematol. 1988 Feb;16(2):131–138. [PubMed] [Google Scholar]
  27. Nakagawa K., Yajima K., Yamashita K., Ikenaka Y., Yokota S., Kakutani T., Kawaharada H., Watanabe K. Constitutive high-level production of human lymphotoxin by CHO-K1 cells transformed with the human lymphotoxin gene controlled by a human beta-actin promoter. Agric Biol Chem. 1991 Feb;55(2):501–508. [PubMed] [Google Scholar]
  28. Nedwin G. E., Naylor S. L., Sakaguchi A. Y., Smith D., Jarrett-Nedwin J., Pennica D., Goeddel D. V., Gray P. W. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361–6373. doi: 10.1093/nar/13.17.6361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nishimura T., Nakamura Y., Takeuchi Y., Tokuda Y., Iwasawa M., Kawasaki A., Okumura K., Habu S. Generation propagation, and targeting of human CD4+ helper/killer T cells induced by anti-CD3 monoclonal antibody plus recombinant IL-2. An efficient strategy for adoptive tumor immunotherapy. J Immunol. 1992 Jan 1;148(1):285–291. [PubMed] [Google Scholar]
  30. Old L. J. Tumor necrosis factor (TNF). Science. 1985 Nov 8;230(4726):630–632. doi: 10.1126/science.2413547. [DOI] [PubMed] [Google Scholar]
  31. Oster W., Lindemann A., Horn S., Mertelsmann R., Herrmann F. Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes. Blood. 1987 Nov;70(5):1700–1703. [PubMed] [Google Scholar]
  32. Papermaster B. W., Gilliland C. D., McEntire J. E., Smith M. E., Buchok S. J. Lymphokine-mediated immunotherapy studies in mouse tumor systems. Cancer. 1980 Mar 15;45(5 Suppl):1248–1253. doi: 10.1002/1097-0142(19800315)45:5+<1248::aid-cncr2820451335>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  33. Patton J. S., Shepard H. M., Wilking H., Lewis G., Aggarwal B. B., Eessalu T. E., Gavin L. A., Grunfeld C. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8313–8317. doi: 10.1073/pnas.83.21.8313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  35. Pober J. S., Lapierre L. A., Stolpen A. H., Brock T. A., Springer T. A., Fiers W., Bevilacqua M. P., Mendrick D. L., Gimbrone M. A., Jr Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J Immunol. 1987 May 15;138(10):3319–3324. [PubMed] [Google Scholar]
  36. Ransom J. H., Evans C. H., DiPaolo J. A. Lymphotoxin prevention of diethylnitrosamine carcinogenesis in vivo. J Natl Cancer Inst. 1982 Sep;69(3):741–744. [PubMed] [Google Scholar]
  37. Rosenberg S. A., Henrichon M., Coyne J. A., David J. R. Guinea pig lymphotoxin (LT). I. In vitro studies of LT produced in response to antigen stimulation of lymphocytes. J Immunol. 1973 Jun;110(6):1623–1629. [PubMed] [Google Scholar]
  38. Ruddle N. H., Waksman B. H. Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity. Science. 1967 Sep 1;157(3792):1060–1062. doi: 10.1126/science.157.3792.1060. [DOI] [PubMed] [Google Scholar]
  39. Ruff M. R., Gifford G. E. Rabbit tumor necrosis factor: mechanism of action. Infect Immun. 1981 Jan;31(1):380–385. doi: 10.1128/iai.31.1.380-385.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sohmura Y., Nakata K., Yoshida H., Kashimoto S., Matsui Y., Furuichi H. Recombinant human tumor necrosis factor--II. Antitumor effect on murine and human tumors transplanted in mice. Int J Immunopharmacol. 1986;8(3):357–368. doi: 10.1016/0192-0561(86)90118-9. [DOI] [PubMed] [Google Scholar]
  41. Spies T., Morton C. C., Nedospasov S. A., Fiers W., Pious D., Strominger J. L. Genes for the tumor necrosis factors alpha and beta are linked to the human major histocompatibility complex. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8699–8702. doi: 10.1073/pnas.83.22.8699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Watanabe N., Niitsu Y., Umeno H., Sone H., Neda H., Yamauchi N., Maeda M., Urushizaki I. Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia. Cancer Res. 1988 Feb 1;48(3):650–653. [PubMed] [Google Scholar]

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