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Therapeutic efficacy of human recombinant interleukin-2 (TGP-3) alone or in combination with cyclophosphamide and immunocompetent cells in allogeneic, semi-syngeneic, and syngeneic murine tumors

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Summary

The potential for a recombinant human interleukin-2 (rIL-2, TGP-3) alone, in combination with cyclophosphamide, and in combination with cyclophosphamide and normal immunocompetent cells to manifest biological activity in vivo was tested using allogeneic, semi-syngeneic, and syngeneic tumor-host systems in mice. The biological activity of rIL-2 was evaluated by the inhibition of the growth of tumors and the inhibition of metastases in short-term assays and, in long-term assays, the prolongation of the survival time of mice bearing subcutaneously (s.c.) or intradermally transplanted tumors. rIL-2 was injected s. c. daily continuously for up to 40 days or intermittently two to four times into mice bearing established tumors. In the short-term assays, the dose and schedule dependence of activity of rIL-2 alone was significantly manifested against sarcoma 180 in ICR mice (allogeneic) by the regression of the tumor, and was confirmed against Meth-A fibrosarcoma in BALB/c mice (syngeneic) by retarding the growth of the tumor. When assessed using these tumors, it was found that the antitumor activity of rIL-2 was scheduledependent: the growth of tumors was more significantly suppressed when rIL-2 was injected every day for 10 days, starting on the 7th day after tumor transplantation, than when rIL-2 was injected five times every other day or twice every 5th day, even if the total amounts of rIL-2 injected were same. The continuous injection for 10 days was considered to be a standard regimen and the daily effective doses of rIL-2 were 5, 10, and 25 µg/mouse. Using the standard regimen and the effective doses, the activity of rIL-2 alone was also observed against two other syngeneic tumors: Colon carcinoma 26 in BALB/c mice, by retarding the growth of the tumor, and Lewis lung carcinoma in C57BL/6 mice by reducing the formation of lung metastases. When assessed using M5076 reticulum cell sarcoma, in a long-term assay, the activity of rIL-2 alone was not manifested in C57BL/6 mice (syngeneic) even when rIL-2 was injected for a long period (20 days) but it was observed in BDF1 (semi-syngeneic) mice. On the other hand, it was found that rIL-2 was effective in combination with cyclophosphamide in prolonging the survival time of C57BL/6 mice bearing the tumor. After cyclophosphamide (2.0 mg) had been administered orally to mice on the 6th day after tumor transplantation, the tumor regressed temporarily but regrew; however, when rIL-2 at a dose of 10 µg was also injected daily for a long period (40 days), the regrowth was retarded and the survival time of the mice was significantly prolonged. Moreover, when normal immunocompetent cells were transferred at the tumor sites, the regrowth of the tumors was retarded more significantly even at a daily dose of 1 µg or 3 µg rIL-2, and mice were observed to be cured by daily doses over 3 µg. The results obtained in the syngeneic tumor-host systems indicate that the continuous injection of rIL-2 is necessary and important for its activity to be manifest in vivo, and that, when combined with cytotoxic drugs and/or with immunocompetent cells, the potential efficacy of rIL-2 is valuable in cancer therapy.

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References

  1. Brunda MJ, Bellantoni D, Sulich V (1987) In vivo anti-tumor activity of combinations of interferon alpha and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int J Cancer 40: 365

    Google Scholar 

  2. Bubeník J, Indrova M (1987) The anti-tumour efficacy of human recombinant interleukin 2. Correlation between sensitivity of tumours to the cytolytic effect of LAK cells in vitro and their susceptibility to interleukin 2 immunotherapy in vivo. Cancer Immunol Immunother 24: 269

    Google Scholar 

  3. Bubeník J, Perlmann P, Indrova M, Simova J, Jandlova T, Neuwirt J (1983) Growth inhibition of an MC-induced mouse sarcoma by TCGF (IL-2)-containing preparations. Cancer Immunol Immunother 14: 205

    Google Scholar 

  4. Bubeník J, Indrova M, Perlmann P, Berzins K, Mach O, Kraml J, Toulcova A (1985) Tumour inhibitory effects of TCGF/IL-2-containing preparations. Preliminary report. Cancer Immunol Immunother 19: 57

    Google Scholar 

  5. Cheever MA, Greenberg PD, Fefer A, Gillis S (1982) Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2. J Exp Med 155: 968

    Google Scholar 

  6. Donohue JH, Rosenstein M, Chang AE, Lotze MT, Robb RJ, Rosenberg SA (1984) The systemic administration of purified interleukin 2 enhances the ability of sensitized murine lymphocytes to cure a disseminated syngeneic lymphoma. J Immunol 132: 2123

    Google Scholar 

  7. Fletcher M, Goldstein AL (1987) Recent advances in the understanding of the biochemistry and clinical pharmacology of interleukin-2. Lymphokine Res 6: 45

    Google Scholar 

  8. Forni G, Giovarelli M, Santoni A (1985) Lymphokine-activated tumor inhibition in vivo. I. The local administration of interleukin-2 triggers non-reactive lymphocytes from tumorbearing mice to inhibit tumor growth. J Immunol 134: 1305

    Google Scholar 

  9. Garzon FT, Salas M, Berger MR, Kirchner H (1986) Effect of interleukin-2 on the manifestation and growth of acetoxymethyl-methylnitrosamine-induced colorectal rat adenocarcinoma. J Cancer Res Clin Oncol 111: 79

    Google Scholar 

  10. Giavazzi R, Alessandri G, Spreafico F, Garattini S, Mantovani A (1980) Metastasizing capacity of tumour cells from spontaneous metastases of transplanted murine tumours. Br J Cancer 42: 462

    Google Scholar 

  11. Gillis S, Smith KA (1977) Long term culture of tumour-specific cytotoxic T cells. Nature 268: 154

    Google Scholar 

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

    Google Scholar 

  13. Hellström KE (1966) Studies on allogeneic inhibition 1. Differential behavior of mouse tumors transplanted to homozygous and F-1 hybrid hosts. Int J Cancer 1: 349

    Google Scholar 

  14. Hinuma S, Onda H, Naruo K, Ichimori Y, Koyama M, Tsukamoto K (1982) Translation of interleukin 2 mRNA from human peripheral blood leukocytes in Xenopus oocytes. Biochem Biophys Res Commun 109: 363

    Google Scholar 

  15. Hinuma S, Naruo K, Shiho O, Tsukamoto K (1986) Characteristics of murine non-specific killer cells induced in vivo by recombinant human interleukin-2. Immunology 59: 251

    Google Scholar 

  16. Hinuma S, Naruo K, Ootsu K, Houkan T, Shiho O, Tsukamoto K (1987) Suppression of pulmonary tumour metastasis in mice by recombinant human interleukin-2: role of asialo GMl-positive cells. Immunol 60: 173

    Google Scholar 

  17. Hosokawa M, Sawamura Y, Morikage T, Okada F, Xu Zhen-Yi, Morikawa K, Itoh K, Kobayashi H (1988) Improved therapeutic effects of interleukin 2 after the accumulation of lymphokine-activated killer cells in tumor tissue of mice previously treated with cyclophosphamide. Cancer Immunol Immunother 23: 25

    Google Scholar 

  18. Iigo M, Sakurai M, Saijo N, Hoshi A (1987) Synergistic effect of recombinant interleukin-2 on the inhibition of growth of adenocarcinoma 755 by mitomycin. Cancer Treat Rep 71: 567

    Google Scholar 

  19. Kato K, Yamada T, Kawahara K, Onda H, Asano T, Sugino H, Kakinuma A (1985) Purification and characterization of recombinant human interleukin-2 produced inEscherichia coli. Biochem Biophys Res Commun 130: 692

    Google Scholar 

  20. Katre NV, Knauf MJ, Laird WJ (1987) Chemical modification of recombinant interleukin 2 by polyethylene glycol increases its potency in the murine Meth A sarcoma model. Proc Natl Acad Sci USA 84: 1487

    Google Scholar 

  21. Lafreniere R, Rosenberg SA (1985) Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res 45: 3735

    Google Scholar 

  22. Langdon SP, Gescher A, Hickman JA, Stevens MF (1984) The chemosensitivity of a new experimental model — the M5076 reticulum cell sarcoma. Eur J Cancer Clin Oncol 20: 699

    Google Scholar 

  23. Langdon SP, Hickman JA, Gescher A, Stevens MF, Chubb D, Vickers LM (1985)N-Methylformamide (NSC 3051): a potential candidate for combination chemotherapy. Eur J Cancer Clin Oncol 21: 745

    Google Scholar 

  24. Maekawa R, Matsumoto M, Kitagawa T, Harada M, Sato K (1986) Effect of recombinant interleukin 2 (R-IL-2) on in vivo growth of murine myeloma X5563. Cancer Immunol Immunother 23: 25

    Google Scholar 

  25. Mulè JJ, Ettinghausen SE, Spiess PJ, Shu S, Rosenberg SA (1986) Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: survival benefit and mechanisms of tumor escape in mice undergoing immunotherapy. Cancer Res 46: 676

    Google Scholar 

  26. Mulè JJ, Yang JC, Lafreniere R, 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

    Google Scholar 

  27. Naruo K, Hinuma S, Kato K, Koyama M, Tada H, Shiho O, Tsukamoto K (1985) Comparison of the biological properties of purified natural and recombinant human interleukin-2. Biochem Biophys Res Commun 128: 257

    Google Scholar 

  28. Naruo K, Hinuma S, Shiho O, Houkan T, Ootsu K, Tsukamoto K (1989) Detection and characterization of anti-tumor effector cells in Meth-A-bearing mice treated with recombinant human interleukin-2. Clin Exp Immunol (in press)

  29. Ootsu K, Kawaji H, Hinuma S, Naruo K (1985) Antitumor activity of purified recombinant human interleukin-2 against murine tumors in vivo. 14th Int Congr Chemother (abstr). University of Tokyo Press, Tokyo, p 230)

    Google Scholar 

  30. Pizza C, Severini G, Menniti D, Vinci CD, Corrado F (1984) Tumour regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. Preliminary report. Int J Cancer 34: 359

    Google Scholar 

  31. Rosenberg SA, Lotz MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Shimpson C, Reichert CM (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313: 1485

    Google Scholar 

  32. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL (1985) Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 161: 1169

    Google Scholar 

  33. Rosenberg SA, Lotz MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, 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

    Google Scholar 

  34. Saijo N, Ozaki A, Nakano H, Sakurai M, Takahashi H, Sasaki Y, Hoshi A (1986) In vivo augmentation to the cytotoxicity of spleen lymphocytes against syngeneic B-16 melanoma cells and the suppression of the artificial metastases in C57BL/6 mice by subcutaneous multiple injections of high dose human recombinant interleukin-2 (rIL-2). J Cancer Res Clin Oncol 111: 182

    Google Scholar 

  35. Saijo N, Ozaki A, Sakurai M, Ishihara J, Takahashi H, Sasaki Y, Hoshi A, Hamburger AW (1986) Reduction of pulmonary metastases of B 16 melanoma by human recombinant interleukin 2 and lymphokine-activated killer cells in immunosuppressed C57BL/6 mice receiving anticancer agent. Jpn J Cancer Res (Gann) 77: 487

    Google Scholar 

  36. Salup RR, Wiltrout RH (1986) Treatment of adenocarcinoma in the peritoneum of mice: chemoimmunotherapy with IL-2-stimulated cytotoxic lymphocytes as a model for treatment of minimal residual disease. Cancer Immunol Immunother 22: 31

    Google Scholar 

  37. Taguchi T, Urushizaki I, Wakui A, Koyama Y, Saito T, Niijima T, Takakura K, Izuo M, Ikeda S, Kondo T, Kimura K, Ohta K, Akaboshi Y, Ogura T, Hattori T (1985) Phase I trial of recombinant interleukin-2 (TGP-3). 14th Int Congr Chemother (abstr). University of Tokyo Press, Tokyo, p 804

    Google Scholar 

  38. Talmadge JE, Phillips H, Schindler J, Tribble H, Pennington R (1987) Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease. Cancer Res 47: 5725

    Google Scholar 

  39. Vaage J (1987) Local and systemic effects during interleukin-2 therapy of mouse mammary tumors. Cancer Res 47: 4296

    Google Scholar 

  40. Vaage J, Pauly JL, Harlos JP (1987) Influence of the administration schedule on the therapeutic effect of interleukin-2. Int J Cancer 39: 530

    Google Scholar 

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

    Google Scholar 

  42. Yamada T, Kato K, Kawahara K, Nishimura O (1986) Separation of recombinant human interleukin-2 and methionyl interleukin-2 produced inEscherichia coli. Biochem Biophys Res Commun 135: 837

    Google Scholar 

  43. Yasumoto K, Miyazaki K, Nagashima A, Ishida T, Kuda T, Yano T, Sugimachi K, Nomoto K (1987) Induction of lymphokine-activated killer cells by intrapleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer. Cancer Res 47: 2184

    Google Scholar 

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Authors and Affiliations

  1. Biology Laboratories, Central Research Division, Takeda Chemical Industries Ltd, 17-85 Jusohonmachi 2-chome, 532, Yodogawaku, Osaka, Japan

    Koichiro Ootsu, Kazunori Gotoh & Takashi Houkan

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  1. Koichiro Ootsu
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  2. Kazunori Gotoh
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  3. Takashi Houkan
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Ootsu, K., Gotoh, K. & Houkan, T. Therapeutic efficacy of human recombinant interleukin-2 (TGP-3) alone or in combination with cyclophosphamide and immunocompetent cells in allogeneic, semi-syngeneic, and syngeneic murine tumors. Cancer Immunol Immunother 30, 71–80 (1989). https://doi.org/10.1007/BF01665956

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