Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1990 Sep;81(9):942–948. doi: 10.1111/j.1349-7006.1990.tb02671.x

Production and Enhanced Anti‐tumor Activity of Tumor Necrosis Factor in Mice Treated with Cyclophosphamide

Yoshihiro Noso 1,✉, Jeanne Becker 1, Gilles Riveau 1, Francoise Audibert 1, Louis Chedid 1
PMCID: PMC5918104  PMID: 2121696

Abstract

We demonstrated recently that the production of tumor necrosis factor (TNF) is induced in normal mice and in the immunosuppressed nude mouse model by the administration of muramyl dipeptide (MDP) derivatives followed by endotoxin (lipopolysaccharide). In the present study, the ability of this treatment to induce the production of TNF in mice receiving cyclophosphamide (CY) was examined. Two days following treatment with high‐dose CY (250 mg/kg), mice exhibited leukocytopenia and drastically reduced splenic weight. However, these animals remained capable of producing TNF, albeit at lower levels, when treated with MDP derivatives and lipopolysaccharide (LPS), particularly when the lipophilic analogue MDP‐dipalmitoyl glycerol (GDP) was utilized. TNF was also induced by the administration of MDP‐GDP and LPS to Meth A sarcoma‐bearing mice treated with this dose of CY. Furthermore, in all animals receiving this combination therapy, sarcoma necrosis and complete regression were obtained without any sign of tumor regrowth. A dose of 100 mg/kg CY was not effective for inhibiting tumor regrowth under the same experimental conditions. These results demonstrated that the anti‐tumor activity of endogenously induced TNF is potentiated by combined therapy with a high dose of CY.

Keywords: Anti‐tumor activity, Tumor necrosis factor, Cyclophosphamide, Mouse

Full Text

The Full Text of this article is available as a PDF (412.7 KB).

REFERENCES

  • 1. ) Carswell , E. A. , Old , L. J. , Kassel , R. L. , Green , S. , Fione , N. and Williamson , B.An endotoxin induced serum factor that causes necrosis of tumor . Proc. Natl. Acad. Sci. USA , 72 , 3666 – 3675 ( 1975. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Beutler , B. , Greenworld , D. , Humes , J. L. , Change , M. , Par , Y. C. E. , Nathison , J. , Ulevitch , R. and Cerami , A.Identity of tumor necrosis factor and the macrophage secreted factor cachectin . Nature , 316 , 552 – 554 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Matthews , N.Tumor necrosis factor from the rabbit. II. Production by monocytes . Br. J. Cancer , 38 , 310 – 315 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Mannel , D. N. , Moore , R. N. and Mergenhagen , S. L.Macrophages as a source of tumoricidal activity (tumor necrotizing factor) . Infect. Immun. , 30 , 523 – 530 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Beutler , B. and Cerami , A.Cachectin: more than a tumor necrosis factor . N. Engl. J. Med. , 316 , 376 – 385 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Beutler , B. and Cerami , A.Cachectin and tumor necrosis factor as two sides of the same biological coin . Nature , 320 , 584 – 588 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Parant , M. , Parant , F. , Vinit , J. C. , Noso , Y. and Chedid , L.Priming effect of muramyl peptides for induction by lipopolysaccharide of tumor necrosis factor production in mice . Cancer Res. , in press . [DOI] [PubMed]
  • 8. ) Noso , Y. , Parant , M. , Parant , F. and Chedid , L.Production of tumor necrosis factor in nude mice by muramyl peptides associated with bacterial vaccines . Cancer Res. , 48 , 5766 – 5769 ( 1988. ). [PubMed] [Google Scholar]
  • 9. ) Hersh , E. M. , Whitecar , J. P. , McCredie , K. B. , Bodey , G. P. and Freireich , E. J.Chemotherapy, immunocompetence, immunosuppression and prognosis in acute leukemia . N. Eng. J. Med. , 285 , 1211 – 1221 ( 1971. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Regenass , U. , Muller , M. , Curschellas , E. and Matter , A.Anti‐tumor effects of tumor necrosis factor in combination with chemotherapeutic agents . Int. J. Cancer , 39 , 266 – 273 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Haranaka , K. , Satomi , N. and Sakurai , A.Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumor in nude mice . Int. J. Cancer , 34 , 263 – 267 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Philips , N. C. , Paraf , A. , Bahr , G. M. and Chedid , L.Modulation of murine lymphoma growth by MDP, MDP (D‐D) and cyclophosphamide. I. Inhibition of growth in vivo . Int. J. Immunopharmacol. , 5 , 219 – 227 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Parant , M.Biologic properties of a new synthetic adjuvant, muramyl dipeptide (MDP) . Springer Semin. Immunopathol. , 2 , 101 – 118 ( 1979. ). [Google Scholar]
  • 14. ) Chedid , L. , Parant , M.Parant , F. and Riveau , G.Non‐specific effects of LPS or bacterial infections . In“The Immunobiology and Immunopharmacology of Bacterial Endotoxins ” ed. Szentivanyi A. and Friedman H. , pp. 201 – 213 ( 1986. ). Plenum Press; , New York . [Google Scholar]
  • 15. ) Parant , M. , Gatelli , A. , Parant , F. and Chedid , L.Role of B lymphocytes in nonspecific resistance to Klebsiella pneumoniae infection of endotoxin treated mice . J. Infect. Dis. , 134 , 531 – 539 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Berendt , M. J. , North , R. J. and Kirsten , D. P.The immunological basis of endotoxin induced tumor regression. Requirement for T‐cell mediated immunity . J. Exp. Med. , 148 , 1550 – 1559 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Mannel , D. N. , Metzler , M. S. and Mergenhagen , S. E.Generation and characterization of a lipopolysaccharide induced and serum derived cytotoxic factor for tumor cells . Infect. Immun. , 28 , 204 – 211 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Watanabe , N. , Sone , H. , Neda , H. , Niitsu , Y. and Urushizaki , I.Mechanisms of production of tumor necrosis factor (TNF). Reconstitution experiment with nude mice . Jpn. J. Cancer Chemother. , 11 , 1284 – 1289 ( 1984. ). [PubMed] [Google Scholar]
  • 19. ) Rull , F. C. , Jr. , Jacobs , S. , Jr. and Cuatrecasa , O.Cellular receptor for 125I‐labeled tumor necrosis factor specific binding, affinity labeling and relationship to sensitivity . Proc. Natl. Acad. Sci. USA , 82 , 5756 – 5760 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Tsujimoto , M. , Yip , Y. K. and Vilcek , J.Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells . Proc. Natl. Acad. Sci. USA , 82 , 7626 – 7630 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Tsujimoto , M. , Feinman , R. and Vilcek , J.Differential effects of type I INF and INF gamma on the binding of tumor necrosis factor to receptor in two human cell lines . J. Immunol. , 137 , 2272 – 2276 ( 1986. ). [PubMed] [Google Scholar]
  • 22. ) Gamble , J. R. , Harlan , J. M. , Klebanoff , S. J. and Vadas , M. A.Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor . Proc. Natl. Acad. Sci. USA , 82 , 8667 – 8671 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Taracey , K. J. , Beutler , B. , Tavry , S. F. , Merryweather , J. , Wolpe , S. , Milsark , I. W. , Hariri , R. J. , Fahey , T. J. , III , Zentella , A. , Albert , J. D. , Shires , G. T. and Cerami , A.Shock and tissue injury induced by recombinant human cachectin . Science , 234 , 470 – 474 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Nowroth , P. P. and Stern , D. M.Modulation of endo‐thelial cell hemostatic properties by tumor necrosis factor . J. Exp. Med. , 164 , 740 – 745 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. ) Bevliacqua , M. P. , Pober , J. S. , Majeau , G. R. , Fiers , W. , Cotran , R. S. and Gimbrone , M. A.Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison to activity of interleukin I . Proc. Natl. Acad. Sci. USA , 83 , 4533 – 4537 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Sato , N.Goto , T. , Haranaka , K. , Satomi , N. , Nariuchi , H. , Mano‐Hirano , T. and Sawasaki , Y.Action of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition and toxicity . J. Natl. Cancer Inst. , 76 , 1113 – 1121 ( 1986. ). [PubMed] [Google Scholar]
  • 27. ) Ehrke , M. J. and Mihich , E.Effects of anti‐cancer agents on immune responses . In “ Trends in Pharmacological Sciences ,” pp. 412 – 417 ( 1985. ). Elsevier Science Publishers B.V. , Amsterdam . [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES