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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 May;79(5):636–646. doi: 10.1111/j.1349-7006.1988.tb00034.x

Potentiation of Antitumor Activity of Macrophages by Recombinant Interferon Alpha A/D Contained in Gelatin Microspheres

Yasuhiko Tabata 1, Kazuko Uno 2,3, Yoshito Ikada 1, Shigeru Muramatsu 2
PMCID: PMC5917552  PMID: 3136117

Abstract

Gelatin microspheres containing recombinant human interferon αA/D (A/D‐IFN) (IFN‐microspheres) potentiated the antitumor activity of mouse peritoneal macrophages (Mφo) much more efficiently than free A/D‐IFN. Mφo acquired the inhibitory activity on tumor cell growth by the ingestion of IFN‐microspheres without the aid of lipopolysaccharide (LPS), though LPS was required as a second signal for activating Mφo primed with free IFN. The IFN‐microspheres were much more efficient than free IFN plus LFS in respect of the IFN amount and the time required for Mφo activation. Furthermore, Mφo pretreated with the IFN‐microspheres maintained their activated state for a much longer period than those pretreated with free A/D‐IFN plus LPS. A monoclonal anti‐IFN‐αA antibody, which was capable of neutralizing A/D‐IFN, did not interfere with the Mφo activation by the IFN‐microspheres. Even human IFN‐αA was effective in activating murine Mφo similarly to A/D‐IFN, when given in the form of IFN‐microspheres, though human IFN‐αA in the free form was ineffective. These results argue that the mechanism of Mφo activation by the IFN‐microspheres is different from that by free IFN.

Keywords: Macrophage activation, Antitumor activity, Phagocytosis, Gelatin microspheres, Interferon‐αA/D

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References

  • 1).Evans , R. and Alexander , D.Mechanism of immunological specific killing of tumor cells by macrophages . Nature , 236 , 168 – 170 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 2).Hibbs , J. B. , Jr.Discrimination between neoplastic and non‐neoplastic cells in vitro by activated macrophages . J. Nail. Cancer Inst. , 35 , 1487 – 1492 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 3).Alexander , P.The functions of the macrophage in malignant disease . Annu. Rev. Med. , 27 , 207 – 224 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 4).Eccles , S. A.Macrophages and cancer . In “ Immunological Aspects of Cancer ,” ed. Castro J. E. , pp . 123 – 154 ( 1978. ). University Park Press; , Blatimore . [Google Scholar]
  • 5).David , J. R.Macrophage activation by lymphocyte mediators . Fed. Proc. , 34 , 1730 – 1736 ( 1975. ). [PubMed] [Google Scholar]
  • 6).Fidler , I. J. , Darnell , J. H. and Budmen , M. B.Tumoricidal properties of mouse macrophages activated with mediators from rat lymphocytes stimulated with concanavalin A . Cancer Res. , 36 , 3608 – 3615 ( 1976. ). [PubMed] [Google Scholar]
  • 7).Gresser , I. , Brouty‐Boye , D. , Thomas , M. T. and Macieira‐Coelho , A.Interferon and cell division. I. Inhibition of the multiplicaton of mouse leukemia L1210 cells in vitro by interferon preparations . Proc. Natl. Acad. Sci. USA , 66 , 1052 – 1058 ( 1970. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8).Uno , K. , Shimizu , S. , Ido , M. , Naito , K. , Inaba , K. , Oka , T. , Kishida , T. and Muramatsu , S.Direct and indirect effects of interferon on in vivo murine tumor cell growth . Cancer Res. , 45 , 1320 – 1326 ( 1985. ). [PubMed] [Google Scholar]
  • 9).Doe , W. F. and Henson , P. M.Macrophage stimulation by bacterial lipopolysaccharide. I. Cytolytic effect on tumor target cells . J. Exp. Med. , 148 , 544 – 556 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10).Sone , S. and Fidler , I. J.Tumor cytotoxicity of rat alveolar macrophages activated in vitro by endotoxin . J. Reticuloendothel. Soc. , 27 , 269 – 279 ( 1980. ). [PubMed] [Google Scholar]
  • 11).Elouz , F. S. , Adam , A. , Ciorbaru , R. and Ledever , E.Minimal structural requirements for adjuvant activity of bacterial peptideglycan derivatives . Biochem. Biophys. Res. Commun. , 59 , 1317 – 1325 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 12).Kotani , S. , Watanabe , Y. and Kinoshita , T.Immunoadjuvant activities of synthetic N‐acetyl‐muramyl peptides or ‐amino acids . Biken. J. , 19 , 9 – 14 ( 1976. ). [PubMed] [Google Scholar]
  • 13).Ledever , E.Synthetic immunostimulants derived from the bacterial cell wall . J. Med. Chem. , 23 , 819 – 823 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 14).Brunda , M. J. , Rosenbaum , D. and Stern , L.Inhibition of experimentally‐induced murine metastases by recombinant alpha interferon: correlation between the modulatory effect of interferon treatment on natural killer activity and inhibition of metastases . Int. J. Cancer , 34 , 421 – 426 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 15).Barlozzari , T. , Leonhardt , J. , Wiltrout , R. H. , Herberman , R. B. and Reynolds , C. W.Direct evidence for the role of LGL in the inhibition of experimental tumor metastases . J. Immunol. , 134 , 2783 – 2789 ( 1985. ). [PubMed] [Google Scholar]
  • 16).Jett , J. R. , Mantovani , A. and Herberman , R. B.Augmentation of human monocytemediated cytolysis by interferon . Cell Immunol. , 54 , 425 – 436 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 17).Kataoka , T. , Matsuura , N. , Ohhashi , 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]
  • 18).Gresser , I. , Bourali , C. , Chouroulinkov , I. , Fontaine‐Brouty‐Boye , D. and Thomas , M. T.Treatment of neoplasia in mice with interferon preparations . Ann. NY Acad. Sci. , 173 , 694 – 707 ( 1970. ). [Google Scholar]
  • 19).Nishimura , J. , Mitsui , K. , Ishikawa , T. , Tanaka , Y. , Yamamoto , R. , Suhara , Y. and Ishitsuka , H.Antitumor and antimetastatic activities of human recombinant (nterferon Alpha A/D . Clin. Exp. Metastasis , 3 , 295 – 304 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 20).Koff , W. C. , Fogler , W. E. , Gutterman , J. and Fidler , I. J.Efficient activation of human blood monocytes to tumoricidal states by liposomes containing human recombinant gamma interferon . Cancer Immunol. Immunother. , 19 , 85 – 89 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21).Saiki , I. and Fidler , I. J.Synergistic activation by recombinant mouse gamma‐inter‐feron and muramyl dipeptide of tumoricidal properties in mouse macrophages . J. Immunol. , 135 , 515 – 523 ( 1985. ). [PubMed] [Google Scholar]
  • 22).Ikada , Y. and Tabata , Y.Phagocytosis of bioactive microspheres . J. Bioact. Compat. Polym. , 1 , 32 – 46 ( 1986. ). [Google Scholar]
  • 23).Tabata , Y. and Ikada , Y.Macrophage activation through phagocytosis of muramyl dipeptide encapsulated in gelatin microspheres . J. Pharm. Pharmacol. , 39 , 698 – 704 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 24).Pestka , S. and Maeda , S.The human inter‐ferons: their purification and sequence, cloning and expression in bacteria, and biological properties . In “ Humoral Factors in Host Defense ,” ed. Yamamoto Y. , pp . 191 – 243 ( 1982. ). Academic Press Inc. , New York . [Google Scholar]
  • 25).Sawicki , E. , Hanser , T. R. , Stanley , T. W. and Elbert , W.The 3‐methyl‐2‐benzothiazolone hydrazone test, sensitive new methods for the detection, rapid estimation, and determination of aliphatic aldehydes . Anal. Chem. , 33 , 93 – 96 ( 1961. ). [Google Scholar]
  • 26).Greenwood , F. C. and Hunter , W. M.The preparation of 131I‐labelled human growth hormone of high specific radioactivity . Biochem. J. , 89 , 114 – 123 ( 1963. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27).Nakano , K. , Hosokawa , T. and Muramatsu , S.Ontogeny of macrophage function. I. Phagocytic activity and A‐cell activity of newborn and adult mouse peritoneal macrophages . Dev. Comp. Immunol. , 2 , 505 – 518 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 28).Meltzer , M. S. , Tucker , R. W. , Sanford , K. K. and Leonard , E. J.Interaction of BCG‐activated macrophages with neoplastic and nonneoplastic cell lines in vitro: quantitation of the cytotoxic reaction by release of tritiated thymidine from prelabeled target cells . J. Natl. Cancer Inst. , 54 , 1177 – 1184 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 29).Ruco , L. P. and Meltzer , M. S.Effective tumoricidal capacity of macrophages from C3H/HeJ mice . J. Immunol. , 120 , 329 – 334 ( 1978. ). [PubMed] [Google Scholar]
  • 30).Madan , P. L. , Luzzi , L. A. and Price , J. C.Microencapsulation of waxy solid: wall thickness and surface appearance studies . J. Pharm. Sci. , 63 , 280 – 284 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 31).Hashida , M. , Takahashi , Y. , Muranishi , S. and Sezaki , H.An application of water‐in‐oil and gelatin‐microsphere‐in‐oil emulsion to specific delivery of anticancer agent into stomach lymphatics . J. Pharmacokinet. Biopharm. , 5 , 241 – 255 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 32).Gudewicz , P. W. , Molnar , J. , Lai , M. Z. , Beezhold , D. W. , Siefring , G. E. , Credo , R. B. , Jr. and Lorand , L.Fibronectin‐mediated uptake of gelatin‐coated latex particles by peritoneal macrophages . J. Cell Biol. , 87 , 427 – 432 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33).Zekorn , D.Modified gelatin as plasma substitutes . Bibl Haematol. , 33 , 33 – 60 ( 1969. ). [DOI] [PubMed] [Google Scholar]
  • 34).Fidler , I. J. , Fogler , W. E. , Kleinerman , E. S. and Saiki , I.Abrogation of species specificity for activation of tumoricidal properties in macrophages by recombinant mouse or human interferon‐encapsulated in liposomes . J. Immunol. , 135 , 4289 – 4296 ( 1985. ). [PubMed] [Google Scholar]
  • 35).Fidler , I. J.Recognition and destruction of target cells by tumoricidal macrophages . Israel J. Med. Sci. , 14 , 177 – 191 ( 1978. ). [PubMed] [Google Scholar]

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