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

Abstract

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-kappaB (NF-kappaB) 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-kappaB 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.