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.
Similar content being viewed by others
References
Alexandroff AB, Jackson AM, O'Donnell MA, James K (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Lamm DL (1992) Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 19:573
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
Morales A, Edinger D, Bruce AW (1976) Intracavity bacillus Calmette Guérin in the treatment of superficial bladder tumours. J Urol 116:180
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
Prescott S, James K, Hargreave TB (1990) Radioimmunoassay detection of interferon-gamma in urine after intravesical BCG therapy. J Urol 144:1248
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
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
Ratliff TL, Haaf EO, Catalona WJ (1986) Interleukin-2 production during intravesical bacillus Calmette-Guérin therapy for bladder cancer. Clin Immunol Immunopathol 40:375
Ratliff TL, Kavoussi LR, Catalona WJ (1988) Role of fibronectin in intravesical BCG therapy for superficial bladder cancer. J Urol 139:410
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
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
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
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-003-0384-9