Effect of the uroprotector sodium 2-mercaptoethane sulfonate (Mesna) on the proliferation of the bladder urothelium in the rat after administration of cyclophosphamide.

Abstract

The chemotherapy of malignant tumors with oxazaphosphorine cytostatics, e.g., cyclophosphamide (CP) and ifosfamide, is limited by their severe urotoxic side effects. As a result of cytotoxic damage, the proliferation of the urinary bladder urothelium is considerably stimulated during an intensive reparative regeneration. The recently developed uroprotector sodium 2-mercaptoethane sulfonate (Mesna) allows regional detoxification limited to the kidneys and lower urinary tract and thus protects against damage by aggressive oxazaphosphorine metabolites. The object of the present quantitative autoradiographic investigation was to study urothelial proliferation in the bladder of rats after administration of CP alone and in combination with Mesna. 20 h after intraperitoneal injection of a single dose of CP alone (100 mg/kg), the urothelium showed a steep rise of the 3H-thymidine (3H-TdR) labeling index which reached a peak of 17.6% at 30 h. Thereafter, the 3H-TdR index rapidly dropped. A second peak of 4.4% was observed after 7 days. With supplementary intravenous administration of a single dose of Mesna (100 mg/kg) 15 min before treatment with CP, the labeling index was substantially lower than after administration of CP alone. Thus, maximal values of only 1.6 and 1.9% were observed at 35 h and 7 days, respectively. Histopathological examination of the bladders showed severe necrotizing and ulcerative cystitis, 10, 20 and 25 h after administration of CP alone whereas with additional treatment with Mesna only slight edema of the lamina propria developed. The results obtained clearly demonstrate the protective action of Mesna on the urothelium of the lower urinary tract against the urotoxic effects of CP.