Advertisement

Biotherapy

, Volume 4, Issue 3, pp 205–214 | Cite as

Clinical trials of bestatin for leukemia and solid tumors

  • K. Ota
  • Y. Uzuka
Article

Abstract

A new immunomodulating agent, bestatin (INN: ubenimex) has low toxicity after long-term oral administration and significantly modifies immunological responses. Prolongation of remission duration and survival was achieved in adult acute nonlymphocytic leukemia with bestatin immunotherapy combined with remission maintenance chemotherapy. Patients with myelodysplatic syndrome (MDS) and chronic myelogenous leukemia (CML) responded to bestatin, and it is noted that cytogenetic remission was obtained in CML. MDS and CML are thought to be a family of clonal malignant disorders in which malignant transformations occurs at the level of the pluripotent stem cell. Bestatin may be capable of modifying the biological-proliferative disequilibrium of the disease, and the therapy opens new and promising prospects in the treatment of both MDS and CML. Randomized controlled studies of bestatin immunotherapy were performed in solid tumors including malignant melanoma, carcinoma of the lung, stomach, bladder, head and neck, and esophagus, and therapeutic benefits on disease free-interval or survival were observed in certain types of these cancers. However, the adjuvant activity of bestatin immunotherapy for these cancers should be further investigated to confirm its activity.

Key words

bestatin cancer immunotherapy leukemia MDS ubenimex 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abe F, Shibuya K, Uchida M, Takahashi K, Horinishi H, Matsuda A, Ishizuka M, Takeuchi T, Umezawa H. Effect of bestatin on syngeneic tumors in mice. Gann 1984; 75: 89–94.Google Scholar
  2. 2.
    Benett JM, Catnovsky D, Daniel MT. Proposal for the classification of the myelodysplastic syndromes. Brit J Haematol 1982; 51: 189–99.Google Scholar
  3. 3.
    Blomgren H, Nalsund I, Esposti PL, Johansen L, Aaskoven O. Adjuvant bestatin immunotherapy in patients with transitional cell carcinoma of the bladder. Cancer Immunol Immunother 1987; 25: 41–6.Google Scholar
  4. 4.
    Bruley-Rosset M, Florentin I, Kiger N, Schulz J, Mathe G. Restoration of impaired immune functions of aged animals by chronic bestatin treatment. Immunology 1979; 38: 75–83.Google Scholar
  5. 5.
    Foon FA, Smalley RV, Riggs CW. The role of immunotherapy in acute myelogenous leukemia. Arch Intern Med 1983; 143: 1726–31.Google Scholar
  6. 6.
    Hattori T, Niimoto M, Saeki T. Prospective randomized controlled study on bestatin (INN: ubenimex) in resectable gastric cancer. In: 16th International Congress of Chemotherapy Proceedings “Bestatin (Ubenimex)” 1989; 30–2.Google Scholar
  7. 7.
    Ikeda S, Ishihara K. Randomized, controlled study by bestatin in the treatment of stage Ib and II malignant melanoma. Int J Immunother 1986; 11: 73–9.Google Scholar
  8. 8.
    Ishizuka M, Masuda T, Kanbayashi N, Fukasawa S, Takeuchi T, Aoyagi T, Umezawa H. Effect of bestatin on mouse immune system and experimental murine tumors. J Antibiot 1980; 33: 642–52.Google Scholar
  9. 9.
    Ishizuka M, Masuda T, Mizutani S, Takeuchi T, Umezawa H. Antitumor cells found in tumor-bearing mice given ubenimex. J Antibot 1987; 40: 697–701.Google Scholar
  10. 10.
    Kimura I, Ohnoshi T, Nakata Y, Terao S. Effect of bestatin on the bone marrow. Jpn J Cancer Chemother 1981; 8: 586–9. (in Japanese)Google Scholar
  11. 11.
    Kumamoto Y, Tsukamoto T, Tamiya T, et al. Clinical research of prevention of recurrence of superficial bladder cancer. Cooperative study of clinical efficacy of bleomycin intravesical instillation and bestatin. Hinyokiyo 1985; 31: 1861–83. (in Japanese)Google Scholar
  12. 12.
    Kumano N, Suzuki S, Oizumi K, Konno K, Himori T, Mitachi Y, Wakui A. Imbalance of T cell subsets in cancer patients and its modification with bestatin, a small molecular immunomodulator. Tokoku J Exp Med 1985; 147: 125–33.Google Scholar
  13. 13.
    Maekawa T, Sonoda Y, Okamoto Y, Tsuda S, Nishida K, Taniwaki M, Abe T, Takino T. Effect of bestatin on human granulocyte-macrophage progenitor cells (CFU-c)in vitro and its possible mechanism of action. J Kyoto Pref Univ Med 1984; 93: 1039–44.Google Scholar
  14. 14.
    Majima H. Phase I clinical study of bestatin. In “Recent Results of Bestatin 1985,” ed. Umezawa H 1980; 67–72 (Japan Antibiotics Research Association, Tokyo).Google Scholar
  15. 15.
    Miyake H, Takeda C, Okuda M, et al. Adjuvant therapy with bestatin for squamous cell carcinoma of the head and neck. Otol Fukuoka 1984; 30: 1142–51. (in Japanese)Google Scholar
  16. 16.
    Mouritzen C, European Lung Cancer Study Group. Bestatin as adjuvant treatment in operated stage I and II Don-small cell lung cancer. In: 16th International Congress of Chemotherapy Proceedings “Bestatin (Ubenimex)” 1989; 33–4.Google Scholar
  17. 17.
    Muller WEG, Schuster DK, Zahn RK, Maidhof A, Leyhansen G, Falke D, Koren R, Umezawa H. Properties and specificity of binding sites for the immunomodulater bestatin on surface of mammalian cells. Int J Immunopharmacol 1982; 4: 393–400.Google Scholar
  18. 18.
    Noma T, Yoshimura N, Yata J. Depressed lymphocyte function of cancer patients and their correction by bestatin (product of Streptomyces olivoreticuli). In: Serrou B, ed. Current concepts in human immunology and cancer immunomodulation. Amsterdam: Elsevier Biomedical Press BV, 1982: 611–6.Google Scholar
  19. 19.
    Ota K, Kurita S, Yamada K, Masaoka T, Uzuka Y, Ogawa N. Immunotherapy with bestatin for acute nonlymphocytic leukemia in adult. Cancer Immunol Immunother 1986; 23: 5–10.Google Scholar
  20. 20.
    Ota K, Ogawa N. Randomized controlled study of chemoimmunotherapy with bestatin of acute nonlymphocytic leukemia in adults. Biomed & Pharmacother 1990; 44: 93–102.Google Scholar
  21. 21.
    Saito K, Miyasato H, Tajima K, Ikeda S. Phase I study of bestatin: (I) a clinical study on determination of an optimal dose of bestatin. Jpn J Cancer Chemother 1983; 10: 211–7. (in Japanese)Google Scholar
  22. 22.
    Saito Y, Uzuka Y. Bestatin (ubenimex) treatment of patients with hematological malignancies. 15th International Cancer Congress, Satellite Symposium, Recent Advances of Bestatin (Ubenimex) 1990.Google Scholar
  23. 23.
    Sato H, Isono K, Nabeya K, et al. Effect of bestatin on primary tumor and prognosis in patients with esophageal carcinoma. J Jpn Soc Cancer Ther 1984; 19: 2312–26. (in Japanese)Google Scholar
  24. 24.
    Takada M, Fukuoka M. Controlled study of ubenimex on inoperable lung cancer. In: 16th International Congress of Chemotherapy Proceedings “Bestatin (Ubenimex)” 1989; 35–7.Google Scholar
  25. 25.
    Takino T, Sawai K, Abe T, Maekawa T, Okamoto Y, Inazawa J, Tsuda S, Nishida K, Taniwaki M, Sonoda Y, Edogawa J, Fujii H, Ohgawasa Y. A phase II study on immunochemotherapy with bestatin for hematological malignancies. J Kyoto Pref Univ Med 1984; 93: 405–12. (in Japanese)Google Scholar
  26. 26.
    Talmadge JE, Lenz BF, Pennington R, Long C, Phillips H, Schneider M, Tribble H. Immunomodulatory and therapeutic properties of bestatin in mice. Cancer Res 1986; 46: 4505–10.Google Scholar
  27. 27.
    Talmadge J, Black PL, Pelus LM, Abe F. Hematopoietic and hematologic properties of bestatin in normal and cyclophosphamide myelosuppressed mice. Biomed & Pharmacother; in press.Google Scholar
  28. 28.
    Talpaz M, Kantarjian H, Kurzrock R, Gutterman JU. Update on therapeutic options for chronic myelogenous leukemia. Sem Hemato 1990; 127(3): 31–6.Google Scholar
  29. 29.
    Umezawa H, Aoyagi T, Suda H, Hamada M, Takeuchi T. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. J Antibiot 1976; 29: 97–9.Google Scholar
  30. 30.
    Uzuka Y, Saito Y. Bestatin treatment of myelodysplastic syndromes (MDS) and the effects of bestatin on hematopoiesis in MDS. Acta Oncol 1990; 29: 803–7.Google Scholar
  31. 31.
    Yasumitsu T, Kotake Y, Nakano N, Ohshima S. A randomized clinical trial of ubenimex in resected lung cancer. In: 16th International Congress of Chemotherapy Proceedings “Bestatin (Ubenimex)” 1989; 38–40.Google Scholar
  32. 32.
    Wish JE, Griffin JD, Kuff DR. Response of preleukemic syndromes to continuous infusion of low-dose cytarabine. New Eng J Med 1983; 309: 1559–602.Google Scholar

Copyright information

© Kluwer Academic Publishers 1992

Authors and Affiliations

  • K. Ota
    • 1
  • Y. Uzuka
    • 2
  1. 1.Nagoya Memorial HospitalNagoyaJapan
  2. 2.School of Medicine, the 3rd Department of MedicineTohoku UniversitySendaiJapan

Personalised recommendations