Prevention and treatment of cyclophosphamide and ifosfamide-induced hemorrhagic cystitis

Free radicals and non-radical reactive molecules as well as several cytokines (e.g. tumor necrosis factor-α and interleukin family) and transcription factors (e.g. nuclear factor-κB and activator protein-1) are now known to take part in the pathogenesis of cyclophosphamide (CP) and ifosfamide (IF) induced hemorrhagic cystitis (HC). When these molecular factors are taken into account pathogenesis of bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells, (2) activates intracellular ROS and NO production (directly or through transcription factors) leading to peroxynitrite production, and (3) finally the elevated peroxynitrite level basically damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to PARP activation, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), and consequently in necrotic cell death. There is no doubt that for an effective prevention against CP-and IF-cystitis all pathophysiological mechanisms must be taken into consideration. Experimental works reporting beneficial effects of antioxidants, iNOS inhibitors, cytokine blockers or hyperbaric oxygen (HBO) treatment, against CP-and/or IF-induced HC exist in literature. In this article, we discussed the possible mechanisms and effectiveness of agents used in addition to mesna to prevent CP-and IF-cystitis. In conclusion, antioxidants, iNOS inhibitors, peroxynitrite scavengers, anti-inflammatory agents, as well as HBO therapy may be added to mesna administration in clinical trials in order to obtain the best protocol to improve quality of patients comfort OVERVIEW Beside their military use, mustard group agents found their way into medical therapy. Several mustards such as nitrogen mustards indeed had been improved for chemical warfare agent. Soon after Second World War, their strong cytotoxic effects found to be useful in the therapy of cancer. Several mustard agents such as cyclophosphamide (CP), a synthetic analogue of CP; ifosfamide (IF), melphalan and chlorambucil have been widely used as antineoplastic agents. All mustards act mainly through alkylating of DNA, and make cells unable to divide. This mechanism is true for both therapeutic and crucial side effects causing dose limitations. Hemorrhagic cystitis (HC) is the main side-effect of CP and IF and still encountered as an important dose-limiting problem. Acrolein is the main responsible molecule of CP-and IF-induced cystitis and mesna (2-mercaptoethane sulfonate) is the commonly used agent to protect against this side-effect [1]. Although mesna has been widely used as an effective agent against CP-induced cystitis, significant HC, defined as an …