title: The Dose-Response Relationship of bacillus Calmette-Guérin and Urothelial Carcinoma Cell Biology.
abstract: Attenuated mycobacterium bacillus Calmette-Guérin is widely used as intravesical immunotherapy of nonmuscle invasive urothelial carcinoma. Currently there are limited data on the relationship between bacillus Calmette-Guérin dose intensity and tumor response. We evaluated the dose-response relationship of bacillus Calmette-Guérin to nonmuscle invasive bladder cancer in vitro using urothelial carcinoma cell lines and in vivo using an orthotopic mouse model.
  
  
  
  Two human urothelial carcinoma cell lines were used to study the effect of bacillus Calmette-Guérin dose on the tumor cell response. Internalization, activation of signaling pathways, gene transactivation, cell viability, lactate dehydrogenase and HMGB1 release were study end points. An orthotopic tumor model was used to compare the effect of different doses on the antitumor efficacy of bacillus Calmette-Guérin.
  
  
  
  Bacillus Calmette-Guérin internalization by urothelial carcinoma cells increased as a function of time and dose with a plateau at higher doses and/or long exposure times. Intracellular signaling demonstrated a similar direct, dose dependent increase. Cytokine expression by urothelial carcinoma cells as a function of dose was variable. Some genes increased progressively but others showed a decrease at the highest dose. While nonviable cell number increased in proportion to dose, the number of cells undergoing necrotic cell death decreased at higher doses. A higher dose of bacillus Calmette-Guérin (1:200) showed a better antitumor effect than a standard dose (1:50) (p <0.01).
  
  
  
  Bacillus Calmette-Guérin dose has a direct impact on urothelial carcinoma cell biology. Increased dose intensity, particularly in nonresponders, may represent a strategy to increase bacillus Calmette-Guérin treatment efficacy.
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: gshah@mcw.edu.
authors.forename: Gopitkumar
authors.initials: G
authors.lastname: Shah
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Guangjian
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Fanghong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: YanLi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.affiliation: Department of Urology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: William A
authors.initials: WA
authors.lastname: See
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000283:Administration, Intravesical; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine
keywords: BCG vaccine; bladder neoplasms; carcinoma; dose-response relationship, immunologic; urothelium