Cell Biology and Toxicology

, Volume 23, Issue 5, pp 303–312 | Cite as

Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation



Cyclophosphamide (CP) and ifosfamide (IF) are widely used antineoplastic agents, but their side-effect of hemorrhagic cystitis (HC) is still encountered as an important problem. Acrolein is the main molecule responsible of this side-effect and mesna (2-mercaptoethane sulfonate) is the commonly used preventive agent. Mesna binds acrolein and prevent its direct contact with uroepithelium. Current knowledge provides information about the pathophysiological mechanism of HC: several transcription factors and cytokines, free radicals and non-radical reactive molecules, as well as poly(adenosine diphosphate-ribose) polymerase (PARP) activation are now known to take part in its pathogenesis. There is no doubt that HC is an inflammatory process, including when caused by CP. Thus, many cytokines such as tumor necrosis factor (TNF) and the interleukin (IL) family and transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) also play a role in its pathogenesis. When these molecular factors are taken into account, pathogenesis of CP-induced bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells; (2) it then activates intracellular reactive oxygen species and nitric oxide production (directly or through NF-κB and AP-1) leading to peroxynitrite production; (3) finally, the increased peroxynitrite level damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to activation of PARP, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide–adenine dinucleotide and adenosine triphosphate, and consequently in necrotic cell death. For more effective prevention against HC, all pathophysiological mechanisms must be taken into consideration.


acrolein cyclophoshamide ifosfamide hemorrhagic cystitis peroxynitrite PARP 



activator protein-1






endothelial nitric oxide synthase


epigallocatechin 3-gallate




glutathione peroxidase


hemorrhagic cystitis






inducible nitric oxide synthase




2-mercaptoethane sulfonate


nicotinamide–adenine dinucleotide


nuclear factor-κB


neuronal nitric oxide synthase


nitric oxide


nitric oxide synthase


superoxide anion (radical)




peroxynitrous acid


platelet-activating factor


poly(adenosine diphosphate-ribose) polymerase


reactive oxygen species


superoxide dismutase


tumor necrosing factor alpha


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© Springer Science + Business Media, Inc. 2007

Authors and Affiliations

  1. 1.Department of PhysiologyGulhane Military Medical AcademyAnkaraTurkey
  2. 2.Gülhane Askeri Tip Akademisi, Fizyoloji Anabilim DaliEtlik, AnkaraTurkey

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