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.

Protective Effect of Seleno-l-Methionine on Cyclophosphamide-Induced Urinary Bladder Toxicity in Rats

“…These can be demonstrated within 24 h of a single dose [18]. The urotoxicity of CP is thought to be due to the formation of acrolein that damages the urothelium [19,20]. In accordance with other studies, the damage caused in this study by CP to the structure of the bladders increased as the dose rose.…”

Protective effect of aminoguanidine against oxidative stress and bladder injury in cyclophosphamide‐induced hemorrhagic cystitis in rat

“…It has been already demonstrated that CP-induced bladder damage involves peroxynitrite formation and protein nitration. 35,36 It is noteworthy to mention that in the present study, CP treatment resulted in marked decrease in the activity of SOD, and pretreatment with AG almost completely prevented the loss of activity as well as reduced bladder damage.…”

Renoprotective effect of the Echinodorus macrophyllus in induced renal injury

“…The primary toxic mechanism involves direct action of acrolein in the proximal tubule, and the secondary action of aldophosphamide -toxic nitrogenous and alkylating compounds -are responsible for the generation of reactive oxygen species. (15,16) This metabolism of cyclophosphamide induces the release of inflammatory cytokines and reactive oxygen species resulting in lipid peroxidation of the cell membrane and consequently, renal injury. (15,16) Thus, the administration of cyclophosphamide chemotherapy induced AKI in rats, which was characterized by reduced glomerular filtration rate, evidenced by a decrease in creatinine clearance.…”

“…(15,16) This metabolism of cyclophosphamide induces the release of inflammatory cytokines and reactive oxygen species resulting in lipid peroxidation of the cell membrane and consequently, renal injury. (15,16) Thus, the administration of cyclophosphamide chemotherapy induced AKI in rats, which was characterized by reduced glomerular filtration rate, evidenced by a decrease in creatinine clearance. The release of oxidative metabolites confirms the mechanism of tubular damage, such as the radical superoxide and hydroxyl, and of intermediate such as peroxides that result in the consumption of antioxidants reserve.…”

“…Studies with different nephrotoxic drugs such as gentamicin, radiocontrasts and other chemotherapeutics reinforce the significant role of oxidative injury in nephrotoxic acute kidney injury. (12,(16)(17)(18) Antioxidants are compounds that attenuate or inhibit the oxidation of cellular protein, lipid peroxidation of the cell membrane and injury of nucleic acids. (7) In this scenario are the medicinal plants.…”