title: Loss of bacillus Calmette-Guérin viability adversely affects the direct response of urothelial carcinoma cells to bacillus Calmette-Guérin exposure.
abstract: OBJECTIVE
  The attenuated mycobacterium bacillus Calmette-Guérin is widely used as intravesical immunotherapy for nonmuscle invasive urothelial carcinoma. Previous studies demonstrated that in the laboratory and clinical settings bacillus Calmette-Guérin viability is a variable that correlates with antitumor efficacy. We evaluated how loss of viability impacted a number of molecular and phenotypic intermediate end points that characterize and/or contribute to the direct effect of bacillus Calmette-Guérin on urothelial carcinoma cells.
  
  
  METHODS
  We studied the effect of loss of bacillus Calmette-Guérin viability on the tumor cell response to the treatment in 2 human urothelial carcinoma cell lines. The cellular response to bacillus Calmette-Guérin rendered nonviable by heat killing was compared to the response to viable bacillus. Response end points included the induction of oxidative stress, activation of intracellular signaling pathways, gene transactivation and phenotypic changes.
  
  
  RESULTS
  Loss of viability resulted in a quantitative decrease in the tumor cell response relative to that of viable bacillus Calmette-Guérin for all measured end points. The decrease in response varied by cell line, ranging from 15% to 100% of the response to viable bacillus. While responses were quantitatively different, nonviable bacillus continued to induce responses that were qualitatively similar to those of bacillus Calmette-Guérin relative to that in untreated controls.
  
  
  CONCLUSIONS
  Bacillus Calmette-Guérin viability is an important variable influencing the direct tumor cell response to the treatment. Although the magnitude of its effects are attenuated, heat killed bacillus Calmette-Guérin remains active for the induction of bacillus Calmette-Guérin responsive biological end points.
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Gopitkumar
authors.initials: G
authors.lastname: Shah
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Guangjian
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Fanghong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: YanLi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.affiliation: Departments of Urology and Biophysics (BK), Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: William
authors.initials: W
authors.lastname: See
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001500:BCG Vaccine / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018384:Oxidative Stress; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine
keywords: BCG vaccine; carcinoma; cell survival; treatment outcome; urinary bladder
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