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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Oct;79(10):1147–1154. doi: 10.1111/j.1349-7006.1988.tb01538.x

Effects of a Combination of Cyclophosphamide and Human Recombinant Interleukin 2 on Pulmonary Metastasis after the Surgical Removal of a 3‐Methylcholanthrene‐induced Primary Tumor in Autochthonous Mice

Masuo Hosokawa 1, Takashi Yabiku 2, Jun‐ichi Ikeda 2, Yutaka Sawamura 3, Futoshi Okada 1, Masashi Komatsumoto 1,2, Tatsuzo Tanabe 2, Hiroshi Kobayashi 1
PMCID: PMC5917638  PMID: 3143703

Abstract

We have investigated the therapeutic effects of a combination of cyclophosphamide (CY, 150 mg/kg, iv) and human recombinant interleukin 2 (IL‐2, 5 × 104 JU/day, ip for 5 days) on autochthonous tumors induced in mice by 3‐methylcholanthrene. The initial treatment was carried out when the tumor had reached 8 to 10 mm in diameter. Twenty‐eight out of 35 mice (80%) died of local recurrence and pulmonary metastasis of tumor cells within 53 × 40 days (mean survival time, MST × SD) after the surgical removal of the primary tumor. When these mice were treated with both CY and IL‐2 following the operation (Op), only 10 out of 20 mice (50%) died of recurrence and metastasis. The survival rate, however, was not improved by CY chemotherapy alone or IL‐2 immnnotherapy alone, although each provided a prolongation of the MST. Natural killer cell and LAK precursor cell activities in the spleen cells from the treated mice were found to be restored by IL‐2 alone or CY + IL‐2, whereas they were suppressed by CY alone. These findings reveal that the restoration of the antitumor activity of spleen cells does not provide an improved therapeutic effect by itself and that IL‐2 immunotherapy requires the associated effect of CY chemotherapy to achieve an improved therapeutic effect.

Keywords: Autochthonous tumor, Interleukin 2, Cyclophosphamide —‐ Pulmonary metastasis

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References

  • 1. ) Hosokawa , M. , Sawamura , Y. , Morikage , T. , Okada , F. , Xu , Z‐Y. , Morikawa , K. , Itoh , K. and Kobayashi , H.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. , 26 , 250 – 256 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Hosokawa , M. , Mizukoshi , T. , Sugawara , M. and Kobayashi , H.Therapeutic effects of PS‐K and busulfan on the recurrent and metastatic diseases after the surgical removal of 3‐methylcholanthrene‐induced autochthonous tumors in C57BL/6 mice . Jpn. J. Cancer Res. (Gann) , 76 , 61 – 67 ( 1985. ). [PubMed] [Google Scholar]
  • 3. ) Hosokawa , M. , Mizukoshi , T. , Morikawa , K. , Xu , Z‐Y. and Kobayashi , H.The therapeutic effects of an immunopotentiator, PS‐K, on 3‐methylcholanthrene‐induced autochthonous tumors in C57BL/6 mice in combination with the surgical removal of primary sites . Cancer Immunol. Immunother. , 22 , 181 – 185 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Devos , R. , Plaelinck , G. , Cheroute , H. , Simons , G. , Degrave , W. , Tayernier , J. , Remaut , E. and Fiers , W.Molecular cloning of human interleukin 2 cDNA and its expression in E. coli . Nucleic Acids Res. , 11 , 4307 – 4323 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Wexler , H. and Rosenberg , S. A.Pulmonary metastasis from autochthonous 3‐methylcholanthrene‐induced murine tumors . J. Natl. Cancer Inst. , 63 , 1393 – 1395 ( 1976. ). [PubMed] [Google Scholar]
  • 6. ) Nishimura , T. , Togashi , Y. , Goto , M. , Yagi , H. , Uchiyama , Y. and Hashimoto , Y.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 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Papa , M. Z. , Yang , J. C. , Vetto , J. T. , Shiloni , E. , Eisenthal , A. and Rosenberg , S. A.Combination effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors . Cancer Res. , 48 , 122 – 129 ( 1988. ). [PubMed] [Google Scholar]
  • 8. ) Mitchell , M. S. , Kempf , R. A. , Harel , W. , Shau , H. , Boswell , W. D. , Lind , S. and Bradley , E. C.Effectiveness and tolerability of low‐dose cyclophosphamide and low‐dose interleukin‐2 in disseminated melanoma . J. Clin. Oncol. , 6 , 409 – 424 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Heppner , G. H. , Dexter , D. L. and Miller , F. R.Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor . Cancer Res. , 38 , 3758 – 3763 ( 1978. ). [PubMed] [Google Scholar]
  • 10. ) Fidler , I. J. and Kripke , M. L.Tumor cell antigenicity, host immunity, and cancer metastasis . Cancer Immunol. Immunother. , 7 , 201 – 205 ( 1980. ). [Google Scholar]
  • 11. ) Kerbel , R. S.Implications of immunological heterogeneity of tumors . Nature , 280 , 358 – 360 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Schirrmacher , V.Shift in tumor cell phenotypes induced by signals from the micro‐environment. Relevance for the immunobiology of cancer metastasis . Immunobiology , 157 , 89 – 98 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Ishidate , M. , Jr.Antigenic specificity of different cell lines of rat ascites hepatoma originating in the same individual . Gann Monogr. Cancer Res. , 16 , 195 – 210 ( 1974. ). [Google Scholar]
  • 14. ) Kidera , Y. and Baba , T.Blood flow‐interrupting hyperthermic chemotherapy on established autochthonous mouse sarcoma induced by 3‐methylcholanthrene . Cancer Res. , 38 , 556 – 559 ( 1987. ). [PubMed] [Google Scholar]
  • 15. ) Tokuzen , R. , Okabe , M. , Nakahara , W. , Azuma , I. and Yamamura , Y.Suppression of autochthonous tumors by mixed implantation with a Nocardia rubra cells‐wall skeleton and related bacterial fractions . Gann , 69 , 19 – 24 ( 1978. ). [PubMed] [Google Scholar]
  • 16. ) Ichinose , Y. , Yasumoto , K. , Tanaka , K. , Yaita , H. and Nomoto , K.Combined treatment of autochthonous 3‐methylcholanthrene‐induced murine tumors by immunotherapy and radiotherapy . Gann , 74 , 143 – 147 ( 1983. ). [PubMed] [Google Scholar]
  • 17. ) Suga , T. , Shino , T. , Maeda , Y. Y. and Chihara , G.Antitumor activity of lentinan in murine syngeneic and autochthonous hosts and its suppressive effect on 3‐methylcholanthrene‐induced carcinogenesis . Cancer Res. , 44 , 5132 – 5137 ( 1984. ). [PubMed] [Google Scholar]
  • 18. ) Hayakawa , K. , Yamashita , T. , Suzuki , K. , Tomita , K. , Hosokawa , M. , Kodama , T. and Kobayashi , H.Comparative immunological studies in rats following cryosurgery and surgical excision of 3‐methylcholanthrene‐induced primary autochthonous tumors . Gann , 73 , 462 – 469 ( 1982. ). [PubMed] [Google Scholar]
  • 19. ) Nagano , N. , Yasumoto , K. , Tanaka , K. , Ichinose , Y. , Yaita , H. and Nomoto , K.Successful regional immunotherapy with cell‐wall skeletons of BCG and Nocardia rubra against autochthonous rat tumors . Gann , 73 , 613 – 617 ( 1982. ). [PubMed] [Google Scholar]

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