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Cytokine-mediated antitumor effect of OK-432 on urinary bladder tumor cells in vitro

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Abstract

Fatal complications from the intravesical instillation of bacillus Calmette-Guérin (BCG) for the treatment of superficial urinary bladder tumors have been reported. OK-432, an immunomodulating agent like BCG, may be an effective and safe agent for the treatment of urinary bladder tumors. We investigated the cytokine-mediated antitumor effect of OK-432 on established human bladder cancer cell lines (T24 and KK-47) in vitro. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were cultured with OK-432 for various periods, and the culture supernatants were used as conditioned media. Cytokines in the culture supernatants were quantified. The antitumor effect of OK-432 was evaluated by colony-forming assays, using the conditioned media as the culture media. The colony survival of T24 and KK-47 cells was significantly inhibited by conditioned media from 24-h cultures of PBMCs incubated with OK-432 at concentrations of 0.05 and 0.1 Klinische Einheit (KE)/ml. Conditioned media from PBMCs cultivated with OK-432 for 7 days at 0.01 and 0.05 KE/ml also significantly inhibited the colony survival of both cell lines. Higher concentrations of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) were detected in conditioned media cultivated with OK-432 for 24 h than in media from PBMCs alone. However, higher concentrations of interferon γ (IFNγ) were detected in conditioned media cultivated with OK-432 for 7 days. Approximately 90% of the inhibition of KK-47 cells by the 24-h conditioned media was neutralized by an anti-TNF monoclonal antibody. The inhibition of T24 cells was neutralized approximately 50% by the same antibody. The inhibition of T24 and KK-47 cells by 7-day conditioned media was completely neutralized by an anti-IFNγ monoclonal antibody. The cultivation of PBMCs with OK-432 inhibited the production of granulocyte-colony-stimulating factor (G-CSF) by PBMCs. The inhibition may play a role in the mechanism of the antitumor effect of OK-432. Urinary bladder tumor cell lines have different sensitivities to cytokines. The cytokines induced by OK-432 vary with the concentration of OK-432 and the culture period. It is suggested that in intravesical instillation of OK-432 for treatment of urinary bladder tumor, the optimal dose and interval of instillation should be considered.

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Authors and Affiliations

  1. Department of Urology, Yamaguchi University School of Medicine, 1144 Kogushi, 755, Ube, Yamaguchi, Japan

    Shigeru Sakano, Tomoyuki Shimabukuro & Katsusuke Naito

  2. Laboratories of Cellular Technology, Otsuka Pharmaceutical Co. Ltd., Tokushima, 771-01, Japan

    Yasukazu Ohmoto

Authors
  1. Shigeru Sakano
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  2. Tomoyuki Shimabukuro
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  3. Yasukazu Ohmoto
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  4. Katsusuke Naito
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Sakano, S., Shimabukuro, T., Ohmoto, Y. et al. Cytokine-mediated antitumor effect of OK-432 on urinary bladder tumor cells in vitro. Urol. Res. 25, 239–245 (1997). https://doi.org/10.1007/BF00942092

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  • DOI: https://doi.org/10.1007/BF00942092

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