Abstract
The antitumor effects of recombinant human interleukin‐2 (rIL‐2), in combination with recombinant human interferon‐α A/D hybrid (rIFN‐α A/D) on colon carcinoma 26 (colon 26) in mice were examined histologically. Colon 26 was transplanted subcutaneously into female BALB/c mice on day 0. The mice bearing the tumor received intramuscular injection of rIL‐2, rIFN‐α A/D or the combination of rIL‐2 and rIFN‐α A/D for 2–10 consecutive days starting on day 7. Mice were killed on days 9, 13, 17 and 21. After day 13, growth of the tumor was significantly suppressed in the mice treated with rIL‐2 or rIFN‐α A/D alone and was stopped in the mice treated with rIL‐2 in combination with rIFN‐α A/D. Histologically, tumor necrosis developed in all treated groups, though the degree was the most severe in the group receiving combination treatment. Many large cells (about 15 30 μm in diameter) infiltrated into the tumor, and they had Thy‐1 surface antigen and many periodic acid‐Schiff‐positive round grannies in the cytoplasm. The incidence of these large granular cells was correlated well with the reduction in tumor weight. The ultrastructural features of the large granular cells were very similar to those of murine large granular lymphocyte‐like cells maintained in vitro in an IL‐2‐containing medium. The present large granular cells appear to be a kind of activated lymphoid cells.
Keywords: Interleukin‐2, Interferon‐α A/D, Colon carcinoma 26, Combination therapy, Large granular cell
Full Text
The Full Text of this article is available as a PDF (995.4 KB).
REFERENCES
- 1. ) Ootsu , K. , Gotoh , K. , Houkan , T. and Kusanagi , T.Studies on the combination therapy of recombinant human interferon α A/D (rIFN‐α A/D) and recombinant human interleukin‐2 (rIL‐2, TGP‐3) in murine tumors . Proc. Jpn. Cancer Assoc, 45th Annu. Meet. , 578 ( 1986. ) ( in Japanese ). [Google Scholar]
- 2. ) Brunda , M. J. , Bellantoni , D. and Sulich , V.In vivo anti‐tumor activity of combinations of interferon α 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 – 371 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Iigo , M. , Sakurai , M. , Tamura , T. , Saijo , N. and Hoshi , A.In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors . Cancer Res. , 48 , 260 – 264 ( 1988. ). [PubMed] [Google Scholar]
- 4. ) Streuli , M , Hall , A , Boll , W. , Stewart , W. E. , Nagata , S. and Weissmann , C.Target cell specificity of two species of human interferons produced in Escherichia coli and of hybrid molecules derived from them . Proc. Natl, Acad. Sci. USA , 78 , 2848 – 2852 ( 1981. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. ) Rehberg , E. , Kelder , B. , Hoal , E. G. and Pestka , S.Specific molecular activities of recombinant and hybrid leukocyte interferons . J. Biol. Chem. , 257 , 11497 – 11502 ( 1982. ). [PubMed] [Google Scholar]
- 6. ) Talmadge , J. E. , Herberman , R. B. , Chirigos , M. A. , Maluish , A. E. , Schneider , M. A. , Adam , J. S. , Philips , H. , Thurman , G. B. , Varesio , L. , Long , C. , Oldham , R. K. and Wiltrout , R. H.Hyporesponsiveness to augmentation of murine natural killer cell activity in different anatomical compartments by multiple injections of various immuno‐modulators including recombinant interferons and interleukin 2 . J. Immunol. , 135 , 2483 – 2491 ( 1985. ). [PubMed] [Google Scholar]
- 7. ) Brunda , M. J. and Rosenbaum , D.Modulation of murine natural killer cell activity in vitro and in vivo by recombinant human interferons . Cancer Res. , 44 , 597 – 601 ( 1984. ). [PubMed] [Google Scholar]
- 8. ) Uno , K. , Shimizu , S. , Ido , M. , Naito , K. , Inaba , K. , Oku , T. , Kishida , T. and Muramatsu , S.Direct and indirect effects of interferon on in vivo murine tumor cell growth . Cancer Res. , 45 , 1320 – 1327 ( 1985. ). [PubMed] [Google Scholar]
- 9. ) Uno , K. , Shimizu , S. , Inaba , K. , Kitaura , M. , Nakahira , K. , Kato , T. , Yamaguchi , Y. and Muramatsu , S.Effect of recombinant human interferon‐α A/D on in vivo murine tumor cell growth . Cancer Res. , 48 , 2366 – 2371 ( 1988. ). [PubMed] [Google Scholar]
- 10. ) Kataoka , T. , Matsuura , N. , Oh‐hashi , F. and Suhara , Y.Treatment regimen and host T‐cell‐dependent therapeutic effect of interferon in mouse solid tumors . Cancer Res. , 45 , 3548 – 3553 ( 1985. ). [PubMed] [Google Scholar]
- 11. ) Chang , A. E. , Hyatt , C. L. and Rosenberg , S. A.Systemic administration of recombinant human interleukin‐2 in mice . J. BioL Response Modif , 3 , 561 – 572 ( 1984. ). [PubMed] [Google Scholar]
- 12. ) Ettinghausen , S. E. , Lipford , E. H. , III , Mule , J. J. and Rosenberg , S. A.Systemic administration of recombinant interleukin 2 stimulates in vivo lymphoid cell proliferation in tissues . J. Immunol. , 135 , 1488 – 1497 ( 1985. ). [PubMed] [Google Scholar]
- 13. ) Hinuma , S. , Onda , H. , Naruo , K. , Ichimori , Y. , Koyama , M. and Tsukamoto , K.Translation of interleukin‐2 mRNA from human peripheral blood leukocytes in Xenopus oocytes . Siochem. Biophys. Res. Commun. , 109 , 363 – 369 ( 1982. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Kato , K. , Yamada , T. , Kawahara , K. , Onda , H. , Asano , H. , Sugino , H. and Kakinuma , A.Purification and characterization of recombinant human interleukin‐2 produced in Escherichia coli . Biochem. Biophys. Res. Commun. , 130 , 692 – 699 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Naruo , K. , Hinuma , S. , Kato , K. , Koyama , M. , Tada , H. , Shiho , O. and Tsukamoto , K.Comparison of the biological properties of purified natural and recombinant human interleukin‐2 . Siochem. Biophys. Res. Commun. , 128 , 257 – 264 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Yamada , T. , Kato , K. , Kawahara , K. and Nishimura , O.Separation of recombinant human interleukin‐2 and methionyl interleukin‐2 produced in Escherichia coli . Biochem. Biophys. Res. Commun. , 135 , 837 – 843 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Hinuma , S. , Naruo , K. , Shiho , O. and Tsukamoto , K.Characteristics of murine non‐specific killer cells induced in vivo by recombinant human interleukin‐2 . Immunology , 59 , 251 – 259 ( 1986. ). [PMC free article] [PubMed] [Google Scholar]
- 18. ) Rubinstein , S. , Familletti , P. C. and Pestka , S.Convenient assay for interferons . J. Viral. , 37 , 755 – 758 ( 1981. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. ) Sainte‐Marie , G.A paraffin embedding technique for studies employing immunofluorescence . J. Histochem. Cytochem. , 10 , 250 – 256 ( 1962. ). [Google Scholar]
- 20. ) Rosenberg , S. A. , Mule , J. J. , Spiess , P. J. , Reichert , C. M. and Schwarz , S. L.Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high‐dose recombinant interleukin 2 . J. Exp. Med. , 161 , 1169 – 1188 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. ) Maekawa , R. , Matsumoto , M. , Kitagawa , T. , Harada , M. and Sato , K.Effect of recombinant interleukin 2(R‐IL2) on in vivo growth of murine myeloma X5563 . Cancer Immunol. Immunother. , 23 , 25 – 30 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. ) Bubenik , J. and Indrova , M.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 – 271 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. ) Vaage , J.Local and systemic effects during interleukin‐2 therapy of mouse mammary tumors . Cancer Res. , 47 , 4296 – 4298 ( 1987. ). [PubMed] [Google Scholar]
- 24. ) Vaage , J. , Pauly , J. L. and Harlos , J. P.Influence of the administration schedule on the therapeutic effect of inter‐leukin . Int. J. Cancer , 39 , 530 – 533 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 25. ) Vaage , J.Local interleukin 2 therapy of mouse mammary tumors of various immunogenicities . Cancer Res. , 48 , 2193 – 2197 ( 1988. ). [PubMed] [Google Scholar]
- 26. ) Ootsu , K. , Gotoh , K. and Hokan , T.Therapeutic efficacy of human recombinant interleukin‐2 (TGP‐3) alone or in combination with cyclophosphamide and immunocom‐petent cells in allogeneic, semi‐syngeneic, and syngeneic murine tumors . Cancer Immunol. Immunother. , 30 , 71 – 80 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. ) Mule , J. J. , Yang , J. C. , Afreniere , R. L. , Shu , S. and Rosenberg , S. A.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 ( 1987. ). [PubMed] [Google Scholar]
- 28. ) Saijo , N. , Ozaki , A. , Nakano , H. , Sakurai , M. , Takahashi , H. , Sasaki , Y. and Hoshi , A.In vivo augmentation of 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 – 186 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. ) Hinuma , S. , Naruo , K. , Ootsu , K. , Houkan , T. , Shiho , O. and Tsukamoto , K.Suppression of pulmonary tumour metastasis in mice by recombinant human interleukin‐2: role of asialo GM1‐positive cells . Immunology , 60 , 173 – 179 ( 1987. ). [PMC free article] [PubMed] [Google Scholar]
- 30. ) Lee , S. H. , Chiu , H. , Rinderknecht , E. , Sabo , W. and Stebbing , N.Importance of treatment regimen of inter‐feron as an antitumor agent . Cancer Res. , 43 , 4172 – 4175 ( 1983. ). [PubMed] [Google Scholar]
- 31. ) Nishimura , J. , Mitsui , K. , Ishikawa , T. , Tanaka , Y. , Yamamoto , R. , Suhara , Y. and Ishitsuka , H.Antitumor and antimetastatic activities of human recombinant inter‐feron alpha A/D . Clin. Exp. Metastasis , 3 , 295 – 304 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 32. ) Yoshie , O. , Aso , H. , Nanjo , M. , Tamura , K. , Ebina , T. and Ishida , N.Antitumor effect of recombinant human interferon α on Meth‐A sarcoma in mice . Jpn. J. Cancer Res. , 77 , 413 – 418 ( 1986. ). [PubMed] [Google Scholar]
- 33. ) Brunda , M. J. , Rosenbaum , D. and Stern , L.Inhibition of experimentally‐induced murine metastases by recombinant α rferon: correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases . Int. J, Cancer , 34 , 421 – 426 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 34. ) Yokoyama , T. , Yoshie , O. , Aso , H. , Ebina , T. and Ishida , N.Inhibition of intravascular mouse melanoma dissemination by recombinant human interferon α A/D . Jpn. J. Cancer Res. , 77 , 80 – 84 ( 1986. ). [PubMed] [Google Scholar]
- 35. ) Brooks , C. G. , Kuribayashi , K. , Sale , G. E. and Henney , C. S.Characterization of five cloned murine cell lines showing high cytolytic activity against YAC‐1 cells . J. Immunol , 128 , 2326 – 2335 ( 1982. ). [PubMed] [Google Scholar]
- 36. ) Dvorak , A. M. , Galli , S. J. , Marcum , J. A. , Nabel , G. , Simonian , H. D. , Goldin , J. , Monahan , R. A. , Pyne , K. , Cantor , H. , Rosenberg , R. D. and Dvorak , H. F.Cloned mouse cells with natural killer function and cloned suppressor T cells express ultrastructural and biochemical features not shared by cloned inducer T cells . J. Exp. Med. , 157 , 843 – 861 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. ) Ikuta , K. , Hattori , M. , Wake , K. , Kano , S. , Honjo , T. , Yodoi , J. and Minato , N.Expression and rearrangement of the α, β and γ chain genes of the T cell receptor in cloned murine large granular lymphocyte lines. No correlation with the cytotoxic spectrum . J. Exp. Med. , 164 , 428 – 442 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. ) Warner , J. F. and Dennert , G.Establishment and cloning of cell lines with natural killer activity in lymphokine‐containing media . In “ Lymphokines: a Forum for Immunoregulatory Cell Products Vol. 6,” ed. Miezel S. D. , pp. 165 – 184 ( 1982. ). Academic Press Inc. , New York ). [Google Scholar]
- 39. ) Stutman , O. and Lattime , E. C.Lymphokines and natural cell‐mediated cytotoxicity . In “ Lymphokines: a Forum for Immunoregulatory Cell Products Vol. 12 “ ed. Pick E. , pp. 107 – 159 ( 1985. ). Academic Press Inc. , New York ). [Google Scholar]
- 40. ) Rosenberg , S. A. and Lotze , M. T.Cancer immunotherapy using interleukin‐2 and interleukin‐2‐activated lymphocytes . Annu. Rev. Immunol. , 4 , 681 – 709 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 41. ) Hook , G. R. , Greenwood , M. A. , Barba , D. , Ikejili , B. , Chen , S. N. , Oldfield , E. H. , Weber , R. J. and Muul , L. M.Morphology of interleukin‐2‐stimulated human peripheral blood mononuclear effector cells killing gliomaderived tumor cells in vitro . J. Natl Cancer Inst , 80 , 171 – 177 ( 1988. ). [DOI] [PubMed] [Google Scholar]
