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The Dose-Response Relationship of bacillus Calmette-Guérin and Urothelial Carcinoma Cell Biology. J Urol 2016 06;195(6):1903-10 PMID: 26694905 PMCID: PMC5796534

Pubmed ID

26694905

DOI

10.1016/j.juro.2015.11.073

Abstract

PURPOSE: 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.

MATERIALS AND METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

Author List

Shah G, Zhang G, Chen F, Cao Y, Kalyanaraman B, See WA

Authors

Balaraman Kalyanaraman PhD Chair, Professor in the Biophysics department at Medical College of Wisconsin
William A. See MD Chair, Professor in the Urologic Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84964576084   5 Citations

MESH terms used to index this publication - Major topics in bold

Adjuvants, Immunologic
Administration, Intravesical
Animals
BCG Vaccine
Carcinoma, Transitional Cell
Cell Line, Tumor
Dose-Response Relationship, Immunologic
Female
Humans
Mice
Mice, Inbred C57BL
Treatment Outcome
Urinary Bladder Neoplasms
jenkins-FCD Prod-336 69ef4a6b262d135130251597d5d39873903802b5