title: Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: study of the mechanism of bacillus Calmette-Guérin immunotherapy.
abstract: OBJECTIVE
  In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured.
  
  
  METHODS
  After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12.
  
  
  RESULTS
  After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively.
  
  
  CONCLUSIONS
  We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.
authors.affiliation: Department of Urology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Shintani
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sawada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kohjimoto
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Uekado
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shinka
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000008:administration & dosage*; D016207:Cytokines / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000652:urine
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016207:Cytokines