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.

Effect of melatonin on apoptosis, proliferation and differentiation of urothelial cells after cyclophosphamide treatment

“…Cyclophosphamide treatment causes destruction of the urothelium followed by rapid regeneration mainly because of the proliferation activity of the remaining cells [20–22]. It happened similarly in the present experiment, as proliferation indices gradually increased from day 1 and reached a peak at day 7 after CP treatment, resulting in a hyperplastic urothelium appearance at days 7 and 14 after CP injection.…”

“…dose of CP causes destruction of the bladder urothelium [16–19], which is accompanied not only by necrosis but also by apoptosis [20]. Surviving cells retain their ability to proliferate and re‐epithelialize the denuded areas [21, 22]. Proliferation already occurs during destruction of the urothelium [19] and is followed by rapid urothelial regeneration, observed as reversible hyperplasia.…”

Hyperplasia as a mechanism for rapid resealing urothelial injuries and maintaining high transepithelial resistance

“…In normal conditions, the urothelium has a very slow cell turnover rate (1% in mouse, 0.1¡0.5% in rats and 1.3% in guinea-pigs) (Hicks 1975;Locher and Cooper 1970;Martin 1972) but, in response to injury, the UCs are capable of very rapid proliferation (14¡15.5% in mouse; 17.6% in rats) (Farsund 1976;Fukushima et al 1981;Kunze et al 1984). These highly proliferative UCs form a hyperplastic urothelium composed of many layers of poorly diVerentiated UCs.…”

Electron Microscopic Investigations of the Cyclophosphamide-Induced Lesions of the Urinary Bladder of the Rat and Their Prevention by Mesna

“…The aim of the electron microscopic investigations reported here was to extend the information already available from macroscopic, histological and autoradio graphic studies [2,11,[14][15][16][17]21], Particular attention was paid to the early stages of the damage as well as to the course of the pathological process. We were also interested in finding out, from a clinical viewpoint, whether the major pathological changes could be pre vented by concurrent prophylaxis with mesna.…”