Skip to main content

Advertisement

SpringerLink
Log in

Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

The mechanism by which bacillus Calmette-Guérin (BCG) mediates antitumor activity has not been clearly established. Specific cytokines in the urine after BCG intravesical instillation therapy may serve as a prognostic factor of treatment response. In this study, various urinary cytokines such as interleukin-1β (IL-1β), IL-2, IL-6, IL-8. IL-10, IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were measured.

Materials and methods

In total 20 patients were treated with BCG intravesical instillation therapy for carcinoma in situ of the bladder . At the completion of the first and eighth instillations, spontaneously voided urine specimens were collected before BCG instillation, every 2 h until 12 h, and thereafter until 24 h. All specimens were ultrafiltrated using an ADVANTEC UK-10 membrane. The cytokines were measured using ELISA and RIA techniques.

Results

Significantly higher levels of IL-2, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were detected in the eighth instillation as compared to the first instillation (p<0.001). After BCG intravesical instillation therapy, treatment failure occurred in 6 of the 20 patients (30%), including primary failure (persistence of CIS) in 3, and de novo failure (tumor recurrence) in 3 with a median follow-up of 46.9 months. Significantly higher production of IL-2, IL-6, IL-8, IL-10, and TNF-α was observed in the responder group than in the non-responder group (p<0.05). Multivariate analysis revealed IL-2 as an independent prognostic cytokine of responder status.

Conclusions

This study indicates that urinary IL-2 at the eighth instillation of BCG may serve as a valuable prognostic factor of treatment efficacy as well as tumor recurrence after treatment.

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

Fig. 1
Fig. 2.

Similar content being viewed by others

References

  1. Alexandroff AB, Jackson AM, O'Donnell MA, James K (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689

    CAS  PubMed  Google Scholar 

  2. Bettex-Galland M, Studer UE, Walz A, Dewald B, Baggiolini M (1991) Neutrophil-activating peptide-1/interleukin-8 detection in human urine during acute bladder inflammation caused by transurethral resection of superficial cancer and bacillus Calmette-Guérin. Eur Urol 19:171

    CAS  PubMed  Google Scholar 

  3. Böhle A, Nowc CH, Ulmer AJ, Musehold J, Gedes J, Hofstetter AG, Flad MD (1990) Elevations of cytokines interleukin-1, interleukin-2 and tumor necrosis factor in the urine of patients after intravesical bacillus Calmette-Guérin immunotherapy. J Urol 144:59

    PubMed  Google Scholar 

  4. De Boer EC, De Jong WH, Steerenberg PA (1992) Induction of interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer. Cancer Immunol Immunother 34:306

    PubMed  Google Scholar 

  5. De Boer EC, Somogyi L, Ruiter GJ de, Reijke TM de, Kurth KH, Schamhart DH (1997) Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer. Urol Res 25:31

    PubMed  Google Scholar 

  6. De Jong WH, De Boer EC, Van der Meijden AP, Vegt P, Steerenberg PA, Debruyne FM, Ruitenberg EJ (1990) Presence of interleukin-2 in urine of superficial bladder cancer patients after intravesical treatment with bacillus Calmette-Guérin. Cancer Immunol Immunother 31:182

    PubMed  Google Scholar 

  7. De Marco R, Ensor J, Hasday J (1992) Tumour-stimulated release of tumour necrosis factor-alpha by human monocyte derived macrophages. Cell Immunol 140:304

    PubMed  Google Scholar 

  8. De Reijke TM, De Boer EC, Kurth KH. Schamhartm DH (1996) Urinary cytokines during intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol 155:477

    PubMed  Google Scholar 

  9. Fleischmann JD, Toossi Z, Ellner JJ, Wentworth DB, Ratliff TL, Imbembo AL (1989) Urinary interleukins in patients receiving intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. Cancer 64:1447

    CAS  PubMed  Google Scholar 

  10. Ikuta Y, Katayama N, Wang L et al. (2002) Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy. Blood 99:3717

    Article  CAS  PubMed  Google Scholar 

  11. Jackson AM, Alexandrov AB, Gribben SC, Esuvarnathan K, James K (1993) Expression and shedding of ICAM-1 in bladder cancer and its immunotherapy. Int J Cancer 55:921

    CAS  PubMed  Google Scholar 

  12. Jackson AM, Prescott S, Hawkyard SJ, James K, Chisholm G (1993) The immunomodulatory effects of urine from patients with superficial bladder cancer receiving intravesical Evans BCG therapy. Cancer Immunol Immunother 36:25

    CAS  PubMed  Google Scholar 

  13. Jackson AM, Alexandroff AB, McIntyre M, Esuvaranathan K, James K, Chisholm GD (1994) Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J Clin Pathol 47:309

    CAS  PubMed  Google Scholar 

  14. Jackson AM, Alexandrov AB, Prescott S, James K (1995) Production of urinary tumour necrosis factors and soluble tumour necrosis factor receptors in bladder cancer patients after bacillus Calmette-Guérin immunotherapy. Cancer Immunol Immunother 40:119

    Article  CAS  PubMed  Google Scholar 

  15. Jackson AM, Alexandroff AB, Kelly RW, Skibinska A, Esuvaranathan K, Prescott S, Chisholm GD, James K (1995) Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy. Clin Exp Immunol 99:369

    CAS  PubMed  Google Scholar 

  16. Jackson AM, Ivshina AV, Senko O et al. (1998) Prognosis of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer by immunological urinary measurements: statistically weighted syndromes analysis. J Urol 159:1054

    CAS  PubMed  Google Scholar 

  17. Kenis G, Teunissen C, Jongh R, Bosmans E, Steinbusch H, Maes M (2002) Stability of interleukin 6, soluble interleukin 6 receptor, interleukin 10 and CC16 in human serum. Cytokine 19:228

    Article  CAS  PubMed  Google Scholar 

  18. Kurisu H, Matsuyama H, Ohmoto Y, Shimabukuro T, Naito K (1994) Cytokine-mediated antitumor effect of bacillus Calmette-Guérin on tumor cells in vitro. Cancer Immunol Immunother 39:249

    Article  CAS  PubMed  Google Scholar 

  19. Lamm DL (1992) Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 19:573

    CAS  PubMed  Google Scholar 

  20. Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG Jr, Pagano F, Alfthan O, Brosman S, Fisher HA, Jakse G (1989) Complications of bacillus Calmette-Guérin immunotherapy: review of 2602 patients and comparison of chemotherapy complications. Prog Clin Biol Res 310:335

    CAS  PubMed  Google Scholar 

  21. Morales A, Edinger D, Bruce AW (1976) Intracavity bacillus Calmette Guérin in the treatment of superficial bladder tumours. J Urol 116:180

    CAS  PubMed  Google Scholar 

  22. Patard JJ, Saint F, Velotti F, Abbou CC, Chopin DK (1998) Immune response following intravesical bacillus Calmette-Guérin instillations in superficial bladder cancer : a review. Urol Res 26:155

    Article  CAS  PubMed  Google Scholar 

  23. Prescott S, James K, Hargreave TB (1990) Radioimmunoassay detection of interferon-gamma in urine after intravesical BCG therapy. J Urol 144:1248

    CAS  PubMed  Google Scholar 

  24. Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF (1992) Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 147:1636

    CAS  PubMed  Google Scholar 

  25. Rabinowitz R, Smith DS, Tiemann DD et al. (1997) Urinary interleukin-8/creatinine level as predictor of response to intravesical bacillus Calmette-Guérin therapy in bladder tumor patients. J Urol 158:1728

    CAS  PubMed  Google Scholar 

  26. Ratliff TL, Haaf EO, Catalona WJ (1986) Interleukin-2 production during intravesical bacillus Calmette-Guérin therapy for bladder cancer. Clin Immunol Immunopathol 40:375

    CAS  PubMed  Google Scholar 

  27. Ratliff TL, Kavoussi LR, Catalona WJ (1988) Role of fibronectin in intravesical BCG therapy for superficial bladder cancer. J Urol 139:410

    CAS  PubMed  Google Scholar 

  28. Saint F, Patard JJ, Maille P, Soyeux P, Hoznek A, Salomon L, De la Taille A, Abbou CC, Chopin DK (2001) T helper lymphocyte urinary cytokine profiles in responding and nonresponding patients after 1 and 2 courses of bacillus Calmette-Guérin for superficial bladder cancer. J Urol 166:2142

    CAS  PubMed  Google Scholar 

  29. Thalmann GN, Dewald B, Baggliolini M, Studer UE (1997) Interleukin-8 expression in the urine after bacillus Calmette-Guérin therapy: a potential prognostic factor of tumor recurrence and progression. J Urol 158:1340

    CAS  PubMed  Google Scholar 

  30. Wang MH, Chen YQ, Gercken J, Ernst M, Böhle A, Flad HD, Ulmer AJ (1993) Specific activation of human peripheral blood gamma/delta+ lymphocytes by sonicated antigens of Mycobacterium tuberculosis: role in vitro in killing human bladder carcinoma cell lines. Scand J Immunol 38:239

    CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank Drs. K. Takai, M. Tsuchida, T. Wada for collecting urine specimens, and Ms. K. Kurafuji for technical support.

Author information

Authors and Affiliations

  1. Department of Urology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi Ube, 755-8505, Yamaguchi, Japan

    Etsuya Watanabe, Hideyasu Matsuyama, Kenji Matsuda, Chietaka Ohmi, Yasuhide Tei, Satoru Yoshihiro & Katsusuke Naito

  2. Cellular Technology Institutes, Otsuka Pharmaceutical Co., 771-0192, Tokushima, Japan

    Yasukazu Ohmoto

Authors
  1. Etsuya Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideyasu Matsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chietaka Ohmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuhide Tei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoru Yoshihiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasukazu Ohmoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katsusuke Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katsusuke Naito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watanabe, E., Matsuyama, H., Matsuda, K. et al. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol Immunother 52, 481–486 (2003). https://doi.org/10.1007/s00262-003-0384-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-003-0384-9

Keywords

Search

Navigation