Skip to main content
SpringerLink
Log in

Antitumor resistance induced by zinostatin stimalamer (ZSS), a polymer-conjugated neocarzinostatin (NCS) derivative

I. Meth A tumor eradication and tumor-neutralizing activity in mice pretreated with ZSS or NCS

  • Original Article
  • Zinostatin Stimalamer, Neocarzinostatin Antitumor Resistance, Tumor-Neutralizing Activity MethA
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarzinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of hostmediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of hostmediated antitumor resistance. In athymic Balb/cnu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected withot transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethaA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumorneutralizing activity beginning 14 days after tumor transplantation. Tumor-neutralizing activity was only induced after MethA transplantation. The effector cells of this tumor-neutralizing activity were Thy1.2+ T lymphocytes that had been passed through a nylonwool column, but no significant augmentation of cell-mediated cytotoxic activity of splenocytes from MethA-eradicated mice was observed in vitro.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Awwad M, North RJ (1989) Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res 49: 1649

    PubMed  Google Scholar 

  2. Ben-Efraim S, Bocian RC, Mokyr ME, Dray S (1983) Increase in the effectiveness of melphalan therapy with progression of MOPC-315 plasmacytoma tumor growth. Cancer Immunol Immunother 15: 101

    PubMed  Google Scholar 

  3. Bookman MA, Swerdlow R, Matis LA (1987) Adoptive chemoimmunotherapy of murine leukemia with helper T lymphocyte clones. J Immunol 139: 3166

    PubMed  Google Scholar 

  4. Carswell EA, Old LJ, Kasel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72: 3666

    PubMed  Google Scholar 

  5. Culo F, Klapan I, Kolak T (1993) The influence of cyclophosphamide on antitumor immunity in mice bearing late-stage tumors. Cancer Immunol Immunother 36: 115

    PubMed  Google Scholar 

  6. Fujita H, Nakayama N, Sawabe T, Kimura K (1970) In vivo distribution and inactivation of neocarzinostatin. Jpn J Antibiot 23: 471

    PubMed  Google Scholar 

  7. Fujiwara H, Fukuzawa M, Yoshioka T, Nakajima H, Hamaoka T (1984) The role of tumor-specific Lyt-1+2−T cells in eradicating tumor cells in vivo. I. Lyt-1+2−T cells do not necessarily require recruitment of host's cytotoxic T cell precursors for implementation of in vivo immunity. J Immunol 133: 1671

    PubMed  Google Scholar 

  8. Fuyama S, Komatsu H, Arai S (1991) Effector phenotypes and mechanisms of antitumor immune reactivity of tumor-immunized and tumor-bearing mice in two syngeneic tumors. Cell Immunol 137: 200

    PubMed  Google Scholar 

  9. Geran RI, Greenberg NH, Macdonald MM, Schumacher AM, Abbott BJ (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3: 51

    Google Scholar 

  10. Goldberg IH (1987) Free radical mechanisms in neocarzinostatin-induced DNA damage. Free Radical Biol Med 3: 41

    Google Scholar 

  11. Greenberg PD, Kern DE, Cheever MA (1985) Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+, 2−T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med 161: 1122

    PubMed  Google Scholar 

  12. Hengst JCD, Mokyr MB, Dray S (1981) Cooperation between cyclophosphamide cytocidal activity and host antitumor immunity in the cure of mice bearing large MOPC-315 tumors. Cancer Res 41: 2163

    PubMed  Google Scholar 

  13. Honjo K, Suhara Y, Kataoka T (1990) Antitumor activity of host T and non-T cells recovered from tumor nodules after interferon therapy. Jpn J Cancer Res 81: 410

    PubMed  Google Scholar 

  14. Kataoka T, Matsuura N, Oh-hashi F, Suhara Y (1985) Treatment regimen and host T-cell-dependent therapeutic effect of interferon in mouse solid tumors. Cancer Res 45: 3548

    PubMed  Google Scholar 

  15. Maeda H (1981) Neocarzinostatin in cancer chemotherapy (review). Anticancer Res 1: 175

    PubMed  Google Scholar 

  16. Maeda H, Takeshita J, Kanamaru R (1979) A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic. Int J Peptide Protein Res 14: 81

    Google Scholar 

  17. Maeda H, Matsumoto T, Konno T, Iwai K, Ueda M (1984) Tailor-making of protein drugs by polymer conjugation for tumor targeting: a brief review on SMANCS. J Protein Chem 3: 181

    Google Scholar 

  18. Maeda H, Ueda M, Morinaga T, Matsumoto T (1985) Conjugation of poly(styrene-co-maleic acid) derivatives to the antitumor protein neocarzinostatin. J Med Chem 28: 455

    PubMed  Google Scholar 

  19. Masuda E, Takemoto T, Tatsuno T, Obara T (1982) Immunosuppressive effect of a trichothecene mycotoxin, Fusarenon-X in mice. Immunology 45: 743

    PubMed  Google Scholar 

  20. Michael R, Mokyr MB (1993) Characterization of the exogenous interleukin-2 requirements for the generation of enhanced antitumor cytotoxicity by thymocytes from low-dose melphalan-treated MOPC-315 tumor bearers. Cancer Immunol Immunother 36: 37

    PubMed  Google Scholar 

  21. Mizushima Y, Sendo F, Miyake T, Kobayashi H (1981) Augmentation of specific cell-mediated immune responses to tumor cells in tumor-bearing rats pretreated with the antileukemia drug busulfan. J Natl Cancer Inst 66: 659

    Google Scholar 

  22. Mokyr MB, Barker E, Weiskirch LM, Yakesue BY, Pyle JM (1989) Importance of Lyt2+T-cells in the curative effectiveness of a low dose of melphalan for mice bearing a large MOPC-315 tumor. Cancer Res 49: 4597

    PubMed  Google Scholar 

  23. Morikawa K, Hosokawa M, Hamada J, Sugawara M, Kobayashi H (1985) Host-mediated therapeutic effects produced by appropriately timed administration of bleomycin on a rat fibrosarcoma. Cancer Res 45: 1502

    PubMed  Google Scholar 

  24. Morikawa K, Hosokawa M, Hamada J (1986) Possible participation of cytocidal macrophages in the therapeutic effect of bleomycin on a transplantable rat fibrosarcoma. Cancer Res 46: 684

    PubMed  Google Scholar 

  25. 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 76: 278

    PubMed  Google Scholar 

  26. Numasaki Y, Takahashi K, Masuda E, Nohara C, Maeda H (1991) Antitumor effects of a new antitumor agent, zinostatin stimalamer (YM881)—effects on experimental tumors in vitro and in vivo. Jpn J Cancer Chemother 18: 2289

    Google Scholar 

  27. Ray PK, Raychaudhuri S (1981) Low-dose cyclophosphamide inhibition of transplantable fibrosarcoma growth by augmentation of the host immune response. J Natl Cancer Inst 67: 1341

    PubMed  Google Scholar 

  28. Sendo F, Miyake T, Fuyama S, Arai S (1978) Spontaneous regression of syngeneic transplanted tumor in rats pretreated with the antileukemia drug busulfan. J Natl Cancer Inst 60: 385

    PubMed  Google Scholar 

  29. Shoval S, Ophir R, Ben-Efraim S (1989) Deficiency in immunocompetence of mice cured from large MOPC-315 plasmacytomas by melphalan therapy. Cancer Immunol Immunother 29: 279

    PubMed  Google Scholar 

  30. Suzuki F, Munakata T, Maeda H (1988) Interferon induction by SMANCS: a polymer-conjugated derivative of neocarzinostatin. Anticancer Res 8: 97

    PubMed  Google Scholar 

  31. Takeshita J, Maeda H, Kanamaru R (1982) In vitro mode of action, pharmacokinetics, and organ specificity of poly(maleic acid-styrene)-conjugated neocarzinostatin, SMANCS. Gann 73: 278

    PubMed  Google Scholar 

  32. Tanaka S, Numasaki Y, Maeda H (1991) Action mechanisms of zinostatin stimalamer (YM881). Jpn J Cancer Chemother 18: 2295

    Google Scholar 

  33. Winn H (1961) Immune mechanisms in homotransplantation. II. Quantitative assay of the immunologic activity of lymphoid cells stimulated by tumor homografts. J Immunol 86: 228

    PubMed  Google Scholar 

  34. Xu Z, Hosokawa M, Morikawa K, Hatakeyama M, Kobayashi H (1988) Overcoming suppression of antitumor immune reactivity in tumor-bearing rats by treatment with bleomycin. Cancer Res 48: 6658

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Medicine Research Laboratory I, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, 305, Tsukuba, Ibaraki, Japan

    Etsuko Masuda

  2. Department of Microbiology, Kumamoto University Medical School, Kumamoto, Japan

    Hiroshi Maeda

Authors
  1. Etsuko Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Masuda, E., Maeda, H. Antitumor resistance induced by zinostatin stimalamer (ZSS), a polymer-conjugated neocarzinostatin (NCS) derivative. Cancer Immunol Immunother 40, 329–338 (1995). https://doi.org/10.1007/BF01519634

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01519634

Key words

Search

Navigation