Abstract
The present study was designed to evaluate the effect of rTNF alone or in combination with other BRMs on human digestive organ cancers. Six kinds of human digestive organ cancer xenografts (esophageal, stomach, colonic, pancreatic, bile duct, and liver cancers: EC-YO, GC-YN, CC-KK, PC-HN, BDC-SN and Li-7, respectively) were transplanted in nude mice, and rTNF was administered at 103, 5 × 103, or 104U/head directly into the tumor 3 times a week for 2 weeks. EC-YO was the most sensitive to rTNF, and intratumoral administration of rTNF at 103 U/head caused tumor regression. PC-HN, CC-KK and GC-YN were relatively sensitive to rTNF, and their growth was significantly inhibited by rTNF at 5 × 103 U/head, however, the tumors regrew after treatment. Li-7 and BDC-SN were resistant to rTNF. The effects of rTNF in combination with recombinant interferon-γ (rIFN-γ), recombinant interleukin-2 (rIL-2), or streptococcal preparation OK-432 were assessed in mice transplanted with GC-YN. All combinations of rTNF at 5 × 103 U/head and other BRMs were more effective than rTNF alone, and GC-YN tumors were completely regressed after treatment with a combination of rTNF and rIFN-γ or rTNF and OK-432. However in all cases, the combination of rTNF at 103 U/head and any other BRM did not improve the effect. Furthermore, the adverse effects of the combinations were more serious than those of rTNF alone.
TNF may still be a useful cytokine, because it can induce the regression of tumors. However, for its clinical application, a method should be developed to reduce its side effects.
Similar content being viewed by others
Abbreviations
- BRM:
-
biological response modifier
- IFN:
-
interferon
- IL-2:
-
interleukin-2
- PBS:
-
phosphate buffer saline
- rIFN-γ :
-
recombinant interferon-gamma
- rIL-2:
-
recombinant interleukin-2
- rTNF:
-
recombinant tumor necrosis factor
- TNF:
-
tumor necrosis factor
References
Sugarman B, Aggarwal BB, Hass PE, Figari IS, Palladino Jr. MA, Shepard HM. Recombinant human tumor necrosis factor-a: effects on proliferation of normal and transformed cellsin vitro. Science 1985; 230: 943–5.
Fransen L, Van der Hyden J, Ruysschaert R, Fiers W. Recombinant tumor necrosis factor: its effect and its synergism with interferon-y on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 1986; 22: 419–26.
Nakano K, Sohmura Y. Recombinant human tumor necrosis factor. I. Cytotoxic activityin vitro. Int J Immunopharmacol 1986; 8: 347–55.
Tsujimoto M, Yip YK, Vilcek J. Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci 1985; 82: 7626–30.
Deatley GB, Naylor MS, Fiers W, Balkwill FR. DNA fragmentation and cytotoxicity caused by tumor necrosis factor is enhanced by interferon-r. Eur J Immunol 1987; 17: 689–93.
Scott-Schimid D, Hornung R, McGrath KM, Paul N, Ruddle NH. Target cell DNA fragmentation is mediated by lymphotoxin and tumor necrosis factor. Lymphokines Res 1987; 6: 195–202.
Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohn WJ, Aggarwal BB, Goeddel DV. Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984; 312: 724–9.
Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB. Cloning and expression inEscherichia coli of the gene from human tumor necrosis factor. Nature 1985; 313: 803–6.
Wang MB, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF. Molecular cloning complementary DNA for human tumor necrosis factor. Science 1985; 228: 149–54.
Blick M, Sherwin SA, Rosenblum M, Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 1987; 47: 2986–9.
Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, Frei III E, Kufe DW. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. J Natl Cancer Inst 1988; 80: 1039–44.
Wiedenmann B, Reichardt P, Rath U, Theilmann L, Schule B, Ho AD, Schlick E, Kempeni J, Hunstein W, Kommerell B. Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas. J Cancer Res Clin Oncol 1989; 115: 189–92.
Bender B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med 1987; 316: 379–85.
Beutler B, Greenwald D, Hulmes JD, Chang M, Pan Y-CE, Mathison J, Uleritch R, Cerami A. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 1985; 316: 552–4.
Taguchi T. Clinical studies of recombinant human tumor necrosis factor (rHu-TNF: PT-050). Therapeutic Res 1987; 7: 198–205.
Niitsu Y, Watanabe N. Cancer therapy by TNF. Med Immunol 1988; 16: 203–9.
Bartsch HH, Pfizenmaier K, Schroder M, Nagel GA. Sytemische versus lokale Therapie mit rekombinatem Tumor-Nekrose-Factor-alpha (r-TNF-alpha) bei Patienten mit fortgeschrittenen Tumoren. Onkologie 1989; 12: 136–41.
Balkwill FR, Lee A, Aldam G, Moodie E, Thomas A, Tavernier J, Fiers W. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res 1986; 46: 399–03.
Winkelhake JL, Stampfl S, Zimmerman RJ. Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models. Cancer Res 1987; 47: 3948–53.
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; 48: 650–3.
Tsujimoto M, Yip YK, Vilcek J. Interferon-γ enhances expression of cellular receptors for tumor necrosis factor. J Immunol 1986; 136: 2441–4.
Ruggiero V, Tavernier J, Fiers W, Baglioni C. Induction of the synthesis of tumor necrosis factor receptors by interferon-γ. J Immunol 1986; 136: 2445–50.
Kirstein M, Baglioni C. Tumor necrosis factor induces synthesis of two proteins in human fibroblasts. J Biol Chem 1986; 261: 9565–7.
Ruggiero V, Latham K, Baglioni C. Cytostatic and cytotoxic activity of tumor necrosis factor on human cancer cells. J Immunol 1987; 138: 2711–7.
Haranaka K, Sakurai A, Satomi N. Antitumor activity of recombinant human tumor necrosis factor in combination with hyperthermia, chemotherapy, or immunotherapy. J B R M 1987; 6: 379–91.
Niitsu Y, Watanabe N, Umeno H, Sone H, Neda H, Yamauchi N, Maeda M, Urushizaki I. Synergistic effects of recombinant human tumor necrosis factor and hyperthermia onin vitro cytotoxicity and artificial metastasis. Cancer Res 1988; 48: 654–7.
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; 48: 650–3.
Nishimura T, Otha S, Sato M, Togashi Y, Goto M, Hashimoto Y. Combination tumor-immunotherapy with recombinant tumor necrosis factor and recombinant interleukin 2 in mice. Int J Cancer 1987; 40: 255–61.
Klapdor R, Franke N, Bahlo M. Combined therapy of xenografts of human pancreatic carcinomas with rTNF-α and mitomycin C. Onkologie 1989; 12: 143–7.
Matsubara S, Suzuki F, Ishida N. Induction of immune interferon in mice treated with a bacterial immunopotentiator, OK-432. Cancer Immunol Immunother 1979; 6: 415.
Ichimura O, Suzuki S, Saito M, Sugawara Y, Ishida N. Augmentation of interleukin 1 and interleukin 2 production by OK-432. Int J Immunopharmacol 1985; 7: 263–70.
Yamamoto A, Nagamuta M, Usami H, Sugawara Y, Watanabe N, Niitsu Y, Urushizaki I. Release of tumor necrosis factor (TNF) into mouse peritoneal fluids by OK-432, a streptococcal preparation. Immunopharmacol 1986; 11: 79–86.
Bonavida B, Katz J, Hoshino T. Mechanism of NK activation by OK-432 (Streptococcus pyogenes). I. Spontaneous release of NKCF and augmentation of NKCF production following stimulation with NK target cells. Cell Immunol 1986; 102: 126–35.
Sakurai Y, Tsukagoshi S, Satoh H, Akiba T, Suzuki S, Takagaki T. Tumor-inhibitory effect of a streptococcal preparation (NSC-B116209). Cancer Chemother Rep 1972; 56: 9–17.
Nio Y, Zighelboim J, Berek JS, Bonavida B. Sensitivity of fresh and cultured ovarian tumor cells to tumor necrosis factor, interferon-alpha 2, and OK-432. Cancer Immunol Immunother 1988; 27: 246–54.
Nio Y, Zighelboim J, Berek JS, Bonavida B. Cytotoxic and cytostatic effects of the streptococcal preparation OK432 and its subcellular fractions on human ovarian tumor cells. Cancer 1989; 64: 434–41.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nio, Y., Shiraishi, T., Tsubono, M. et al. In vivo effects of human recombinant tumor necrosis factor alone and in combination with other biological response modifiers on human digestive organ cancer xenografts transplanted in nude mice. Biotherapy 3, 337–344 (1991). https://doi.org/10.1007/BF02221326
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02221326