Skip to main content
Log in

Antitumor effects of a new interleukin-2 slow delivery system on methylcholanthrene-induced fibrosarcoma in mice

  • Original Papers
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Summary

The interleukin-2 (IL-2) mini-pellet, the carrier material of which is a biocompatible and biodegradable atelocollagen refined from bovine skin, contains 1×106 units of IL-2 and can release IL-2 slowly in vivo by diffusion and dissolution. We have evaluated the antitumor effects of the IL-2 mini-pellet on an established solid murine tumor, methylcholanthrene-induced fibrosarcoma (Meth A). The subcutaneous administration of the IL-2 mini-pellet alone on days 8 and 11 after tumor inoculation significantly inhibited tumor growth. A significant inhibition was also seen when it was combined with the intravenous injection of 5×107 lymphokine-activated killer (LAK) cells, in comparison to the untreated controls. Moreover, therapy with the IL-2 mini-pellet alone or in combination with LAK cells also prolonged the survival of mice bearing Meth A fibrosarcoma. In order to determine the precise mechanism of action of these antitumor effects, we tested splenocytes of treated mice for cytotoxic activity in vitro and investigated tumor tissues by an immunohistochemical method. On day 2 after the administration of the IL-2 mini-pellet, the lytic activity of splenocytes against both YAC-1 and JTC-11 cells (i.e. NK and LAK activity) was significantly augmented, and on day 7 a massive accumulation of lymphocytes, which were mainly like Thy1+ and/or asialo-GM1+ LAK cells, was seen in the tumor. These findings indicate that the IL-2 mini-pellet is an appropriate system for local administration of IL-2 and can induce LAK-like effector cells at the target site.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

NK:

natural killer

IL-2:

interleukin-2

LAK:

lymphokine-activated killer

PBS:

phosphate-buffered saline

References

  • Cheever MA, Thompson JA, Kern DE, Greenberg PD (1985) Interleukin 2 (IL-2) administrated in vivo: influence of IL-2 route and cell growth. J Immunol 134:3895–3900

    Google Scholar 

  • Cotran RS, Pober JS, Gimbrone MA, Springer TA, Wiebke EA, Gaspari AA, Rosenberg SA, Lotze MT (1987) Endothelial activation during interleukin 2 immunotherapy. A possible mechanism for the vascular leak syndrome. J Immunol 139:1883–1888

    Google Scholar 

  • Donohue JH, Rosenberg SA (1983) The fate of interleukin 2 after in vivo administration. J Immunol 130:2203–2208

    Google Scholar 

  • Ettinghausen SE, Rosenberg SA (1986) Immunotherapy of murine sarcomas using lymphokine activated killer cells: optimization of the schedule and route of administration of recombinant interleukin 2. Cancer Res 46:2784–2792

    Google Scholar 

  • Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human periperal blood lymphocytes. J Exp Med 155:1823–1841

    Google Scholar 

  • Hank JA, Kohler PC, Hillman GW, Rosenthal N, Moore KH, Storer B, Minkoff D, Bradshaw J, Bechhofer R, Sondel PM (1988) In vivo induction of the lymphokine-activated killer phenomenon: interleukin 2-dependcnt human non-major histocompatibility complex-restricted cytotoxicity generated in vivo during administration of human recombinant interleukin 2. Cancer Res 48:1965–1971

    Google Scholar 

  • Herberman RB, Hiserodt J, Vujanovic N, Balch C, Lotzova E, Bolhuis R, Golub S, Lanier LL, Phillips JH, Riccardi C, Ritz J, Santoni A, Schmidt RE, Uchida A (1987) Lymphokine activated killer cell activity. Characteristics of effector cells and their progenitors in blood and spleen. Immunol Today 8:178–181

    Google Scholar 

  • Matsuoka J, Sakagami K, Shiozaki S, Uchida S, Fujiwara T, Gohchi A, Orita K (1988) Development of an interleukin-2 slow delivery system. Trans Am Soc Artif Intern Organs 34:729–731

    Google Scholar 

  • Morgan DA, Ruscetti FW, Gallo RC (1976) Selective in vivo growth of T lymphocytes from normal human bone marrows. Science 193:1007

    Google Scholar 

  • Mule JJ, Yang JC, Afreniere RL, Shu S, Rosenberg SA (1987) Identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. J Immunol 139:285–294

    Google Scholar 

  • Nishimura T, Togashi Y, Goto M, Yagi H, Uchiyama Y, Hashimoto Y (1986) Augmentation of the therapeutic efficacy of adoptive tumor immunotherapy by in vivo administration of slowly released recombinant interleukin 2. Cancer Immunol Immunother 21:12–18

    Google Scholar 

  • Ono M, Tanaka N, Orita K (1986) Complete regression of mouse hepatoma transplanted after partial hepatectomy and the immunological mechanism of such regression. Cancer Res 46:5049–5053

    Google Scholar 

  • Riccardi C, Giampietri A, Migliorati G, Cannarile L, D'Adamio L, Herberman RB (1986) Generation of mouse natural killer (NK) cell activity: effect of interleukin 2 (IL-2) and interferon (INF) on the in vivo development on natural killer cells from bone marrow (BM) progenitor cells. Int J Cancer 38:553–562

    Google Scholar 

  • Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WN, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and interleukin 2 or high-dose interleukin 2 alone. N Engl J Med 316:889–897

    Google Scholar 

  • Rosenstein M, Ettinghausen SE, Rosenberg SA (1986) Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 137:1735–1742

    Google Scholar 

  • Rubin AL, Stenzel KH, Miyata T, White MJ (1973) Collagen as a vehicle for drug delivery. J Clin Pharmacol 13:309–314

    Google Scholar 

  • Russio JL, Ranger H, Rice R, Johnson E, Bookman M, Steis RG, Londo DL, Urba WJ (1987) IL-2 levels and in vivo induction ofγ-interferon in ascites and sera of cancer patients during intraperitoneal LAK cell-IL-2 therapy. Proc Am Soc Clin Oncol 6:250

    Google Scholar 

  • Shaw J, Caplan B, Paetkau LM, Delovitch TL, Mckenzie IFC (1980) Cellular origins of co-stimulator (IL-2) and its activity in cytotoxic T lymphocyte responses. J Immunol 124:2231–2239

    Google Scholar 

  • Takenaka H, Takada Y, Fujioka K (1986) New formulation of bioactive materials. Pharm Technol Jpn 2:7–15

    Google Scholar 

  • Taniguchi T, Matsui H, Fujita T, Takioka C, Kashima N, Yoshimoto R, Hamuro J (1983) Structure and expression of a cloned cDNA for human interleukin 2. Nature 302:305

    Google Scholar 

  • Wagner H, Rollinghoff M (1978) T-T cell interactions during in vitro cytotoxic allograft responses. Soluble products from activated Lyl+ T cells trigger autonomously antigen-primed Ly2,3+ T cells to cell proliferation and cytolytic activity. J Exp Med 148:1523–1538

    Google Scholar 

  • West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldhan RK (1987) Constant-infusion recombinant interleukin 2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujiwara, T., Sakagami, K. & Orita, K. Antitumor effects of a new interleukin-2 slow delivery system on methylcholanthrene-induced fibrosarcoma in mice. J Cancer Res Clin Oncol 116, 141–148 (1990). https://doi.org/10.1007/BF01612668

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01612668

Key words

Navigation