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Masui, T., Mann, A.M., Macatee, T.L., Okamura, T., Garland, E.M., Smith, R.A. and Cohen, S.M. (1992) Absence of ras oncogene activation in rat urinary bladder carcinomas induced by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine. Carcinogenesis, 13, 2281-2285. doi:10.1093/carcin/13.12.2281

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• TITLE: Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium

  AUTHORS: Francis M. Hughes, Alexa G. Corn, Andrew R. Nimmich, Jeffery D. Pratt-Thomas, J. Todd Purves

  KEYWORDS: Cystitis; Cyclophosphamide; Apoptosis; Bladder; Urothelium

  JOURNAL NAME: Advances in Bioscience and Biotechnology, Vol.4 No.8B, August 8, 2013

  ABSTRACT: Hemorrhagic cystitis (HC) affects a significant number of patients undergoing cyclophosphamide (CP) chemotherapy despite treatment with 2-mercaptoethane sulfonate (Mesna) to inactivate the metabolite acrolein. While the mechanism is unknown, there is clearly acrolein-independent damage to the urothelium. In this study we have explored the induction of apoptosis in the urothelium as a marker of damage and the mechanism underlying the acrolein-independent apoptosis. Two waves of apoptosis (measured as caspase-3/7 activity and Poly (ADP-ribosyl) polymerase (PARP) cleavage) were detected following CP administration, one peaking at 2 h and a second at 48 h. The first wave was not blocked by Mesna, indicating it was independent of acrolein. Caspase-1 was also active at 2 h and activation of caspase-3/7 was blocked by a caspase-1 inhibitor, but not an IL-1 receptor antagonist, suggesting the direct activation of caspase-3/7 by caspase-1 without the need for IL-1 as an intermediate. Our results indicate that CP initiates an early, acrolein-independent wave of apoptosis that results from direct cleavage of caspase-3/7 by caspase-1.