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Cell-mediated immunity is enhanced by cytostatic drugs continuously released at the site of antigenic stimulation

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Summary

Immunopotentiation by cytostatic drugs continuously released from osmotic minipumps, was investigated in a guinea-pig contact-sensitivity model. These pumps are designed to release their content within a period of 7 days. Vepesid (VP-16) and 5-fluorouracil were released into oxazolone-stimulated lymph nodes by subcutaneous implantation of pumps containing either of these drugs. The pumps were implanted at the intended sensitization site, 2 days before sensitization. Strong potentiation of T-cell-mediated immunity, evaluated by delayed-type hypersensitivity measurements, was observed with both drugs tested. Daily injections with VP-16 also caused an enhancement of the immune response. However, daily injections with 5-fluorouracil, a drug assumed to be cell-cycle-specific in its action, failed to potentiate delayed hypersensitivity to oxazolone. Intralesional administration of cytostatic drugs has been put forward as an effective treatment modality in various types of cancer. Therapeutic effects may depend on both local tumorcytotoxic and immunopotentiating activities. Our present results suggest that osmotic minipumps can be applied to broaden the applicability and effectiveness of local chemotherapy.

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References

  1. Bast RC Jr, Segerling M, Ohanian SH, Greene SL, Zbar B, Rapp HJ, Borsos T (1976) Regression of established tumors and induction of tumor immunity by intratumor chemotherapy. J Natl Cancer Inst 56(4):829

    Google Scholar 

  2. Berd M, Mastrangelo MJ, Engstro PF, Paul A, Magnire M (1982) Augmentation of the human immune response by cyclophosphamide. Cancer Res 42:4862

    Google Scholar 

  3. Berd D, Maquire HC Jr, Mastrangelo MJ (1984) Potentiation of human cell mediated immunity by low dose cyclophosphamide. Cancer Res 44:5439

    Google Scholar 

  4. Bier J, Bier H, Siegel T, Ohanian SH, Borsos T, Rapp H (1980) Intralesional chemotherapy of line 10 tumors in strain 2 guinea pigs. Cancer Immunol Parasite Immunol 97:125

    Google Scholar 

  5. Bier J, Bier H, Kleinschuster S, Rapp H (1982) Intratumoral BCG therapy of transplanted head and neck tumors in strain 2 guinea pigs. Head Neck Surg 4:457

    Google Scholar 

  6. Boerrigter GH, Scheper RJ (1984) Local administration of the cytostatic drug 4-hydroperoxy-cyclophosphamide (4-HPCY) facilitates cell-mediated immune reactions. Clin Exp Immunol 58:161

    Google Scholar 

  7. Boerrigter GH, de Groot J, Vos A, Scheper RJ (1984) Potentiation of T-cell mediated immunity by local chemotherapy. Agents Actions 15:77

    Google Scholar 

  8. Diamantstein T, Klos M, Hahn H, Kaufmann SHE (1981) Direct in vitro evidence for different susceptibilities to 4-hydroperoxycyclophosphamide of antigen-primed T cells regulating humoral and cell-mediated immune responses to sheep erythrocytes: a possible explanation for the inverse action of cyclophosphamide on humoral and cell-mediated immune responses. J Immunol 126 (5):1717

    Google Scholar 

  9. Dye ES and North RJ (1981) T-cell-mediated immunosuppression as an obstacle to adoptive immunotherapy of the P815 mastocytoma and its metastases. J Exp Med 154:1033

    Google Scholar 

  10. Eggermont AM, Weimar W, Tank B, Dekkers-Bijma AM, Marquet RL, Lameris JS, Westbroek DL, Jeekel J (1986) Clinical and immunological evaluation of 20 patients with advanced colorectal cancer treated with high dose recombinant leukocyte interferon-αA (rINF-αA). Cancer Immunol Immunother 21:81

    Google Scholar 

  11. Goto M, Mitsuoka A, Sugiyama M, Kitano M (1981) Enhancement of delayed hypersensitivity reaction with varieties of anti-cancer drugs. J Exp Med 154:204

    Google Scholar 

  12. Issell BF, Muggia FM, Carter SK (1984) In: Etoposide (VP-16), current status and new developments. Academic Press London, p 4

    Google Scholar 

  13. Katz SI, Parker D, Turk JL (1974) B-cell suppression of delayed hypersensitivity reactions. Nature 251:550

    Google Scholar 

  14. Kaufmann SHE, Hah H, Diamantstein T (1980) Relative susceptibilities of T-cell subsets involved in delayed-type hypersensitivity to sheep red blood cells to the in vitro action of 4-hydroperoxycyclophosphamide. J Immunol 125:1104

    Google Scholar 

  15. Key ME, Hanna MG Jr (1982) Antigenic heterogenicity of the guinea pig line 10 hepatocarcinoma: implication for active specific immunotherapy. Cancer Immunol Immunother 12:211

    Google Scholar 

  16. Knegt PP, de Jong PC, van Andel JG, de Boer MF, Eykenboom W, van der Schans E (1985) Carcinoma of the paranasal sinuses; results of a prospective pilot study. Cancer 56:57

    Google Scholar 

  17. Maquire HC (1976) Specific acquired immune responsiveness to contact allergens with cyclophosphamide in the mouse. Int Arch Allergy Appl Immun 50:651

    Google Scholar 

  18. Nishimura T, Togashi Y, Goto M, Yagi H, Uchiyama Y, Hashimoto Y (1986) Augmentation of the therapeutic efficacy of adoptive tumor immunotherapy by in vivo administration of slowly released recombinant interleukin 2. Cancer Immunol Immunother 21:12

    Google Scholar 

  19. North RJ, Dye ES (1985) Ly 1+2− suppressor T cells down-regulate the generation of Ly 1−2+ effector T cells during progressive growth of the P815 mastocytoma. Immunology 54:47

    Google Scholar 

  20. Ozer H, Cowens JW, Colvin M, et al. (1982) In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. J Exp Med 155:276

    Google Scholar 

  21. Rollinghoff M, Starzinski-Powitz A, Pfizenmaier K, et al. (1977) Cyclophosphamide-sensitive T-lymphocytes suppress the in vitro generation of antigen-specific cytotoxic T-lymphocytes. J Exp Med 145:455

    Google Scholar 

  22. Sahasrabudhe DM, Dekernion JB, Pontes JE, Ryan DM, O'Donnal RW, Marquis DM, Mudholkar GS, McCune (1986) Specific immunotherapy with suppressor function inhibition for metastatic renal cell carcinoma. J Biol Response Modif 5:581

    Google Scholar 

  23. Scheper RJ, Baak JPA, Hiisivara S, Veldhuizen RW (1975) RRBC and EAC rosette formation after DNCB contact sensitization and cyclophosphamide treatment of guinea pigs. Immunology 29:909

    Google Scholar 

  24. Scheper RJ, Vos A, de Groot J, Boerrigter GH (1984) Evaluation of various cytostatic drugs as local immunotherapeutic agents. Invest New Drugs 2:221

    Google Scholar 

  25. Shu S, Steerenberg PA, Hunter JT, Evans CH, Rapp HJ (1981) Adoptive immunity to the guinea pig line 10 hepatocarcinoma and the nature of in vitro lymphoid tumor cell interactions. Cancer Res 41:3499

    Google Scholar 

  26. Steger G, Dittrich C, Eichler HG, Flener R, Moser K (1987) Interferon alpha 2C in the treatment of 2 patients with AIDS-associated Kaposi sarcoma. Wien Klin Wochenschr 99 (4):120

    Google Scholar 

  27. Tan BTG, Limpens J, Koken M, Valster H, Scheper RJ (1986) Local administration of various cytostatic drugs after subcutaneous immunization enhances delayed-type hypersensitivity reaction to sheep red blood cells in mice. Scand J Immunol 23:605

    Google Scholar 

  28. Turk JL, Parker D (1982) Effect of cyclophosphamide on immunological control mechanisms. Immunol Rev 65:99

    Google Scholar 

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Authors and Affiliations

  1. Dept. of Pathology, Free University Hospital, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Anke M. E. Claessen, Henriëtte Valster, Herman Bril & Rik J. Scheper

  2. Department of Surgery, the Free University Hospital, Amsterdam, the Netherlands

    Sybren Meyer

Authors
  1. Anke M. E. Claessen
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  2. Henriëtte Valster
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  3. Herman Bril
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  4. Sybren Meyer
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  5. Rik J. Scheper
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Claessen, A.M.E., Valster, H., Bril, H. et al. Cell-mediated immunity is enhanced by cytostatic drugs continuously released at the site of antigenic stimulation. Cancer Immunol Immunother 28, 131–135 (1989). https://doi.org/10.1007/BF00199113

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  • DOI: https://doi.org/10.1007/BF00199113

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