Search

It was the object of the present animal experiments to test whether phenacetin (PH) exerts a complete solitary carcinogenic effect on the quiescent and rapidly proliferating urothelium of the lower urinary tract of the rat. In order to stimulate proliferative activity resection of one-third of the urinary bladder was performed which is known to induce intensive reparative regeneration in the stump. PH was administered either continuously with the diet or by gavage in three single doses when proliferative activity was highest. After an experimental period of 2 years 74-83% of the animals receiving PH continuously and 49-52% of the rats after limited gavage feeding had developed uni- and bilateral hyperplasia of the epithelium of the renal papilla. Histologically, the papillary hyperplasia exhibited urothelial differentiation and a typical endophytic growth pattern. It was always associated with healed or, rarely, fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla has to be considered not a true preneoplastic, but rather a reactive proliferative lesion in the sense of a reparative hyperregeneration due to toxic necroses. There was no evidence for a complete solitary carcinogenic action of PH on the urothelium of the entire lower urinary tract. It seems most likely that a metabolite of PH realizes tumor growth only as cocarcinogen with initiation-stimulating and/or initiation-promoting effects acting together with other causative factors during multifactorial multistage carcinogenesis. Based upon the experimental findings reported here, the concept of PH as a solitary complete urothelial carcinogen for man should be reassessed.

Acute rhabdomyolysis with myoglobinuric renal failure occurred in a 66-year-old woman who was in hyperosmolar non-ketotic diabetic coma. No previous description of such a case has been found. The clinical picture was characterized by the typical findings of hyperosmolar coma, in addition to excessive serum creatine kinase and myoglobin levels and massive myoglobinuria with acute renal failure. The rhabdomyolysis became fully manifest only under insulin treatment, possibly the result of insulin-induced hypophosphataemia, which seems to be of importance in the causation of the rhabdomyolysis.

In the present experiments an attempt was made to synchronize urothelial proliferation in the urinary bladder of rats stimulated by either a partial cystectomy (one-third resection) or a single i.p. administration (100 mg/kg) of CP. To temporarily inhibit DNA synthesis HU was given intraperitoneally in multiple fractionated doses (0.1 mg/g each) at hourly intervals during the period of most pronounced proliferative activity between 33 and 55 h after partial cystectomy and between 26 and 44 h after injection of CP. Following partial cystectomy the 3H-TdR index rapidly increased after termination of the HU administration reaching peak values of 54% and 56% at 6 and 8 h, respectively. Thereafter, there was a sharp decline of the percentage of DNA synthesizing cells within 2 h to 24% at 10 h. Then 16 h after removal of the HU block the 3H-TdR index amounted to 15%. At 20 h the labeling increased again to 22%, indicating that the initially blocked cells were capable of going through another cell cycle. After 1 week the 3H-TdR index was 2.5% and after 15 days 0.2%. Synchronously with the decrease of DNA synthesis the mitotic index rapidly increased reaching a maximum value of 4.3% at 10 h. The total fraction of 3H-TdR-labeled cells (growth fraction) was 57%. Following administration of CP 3H-TdR incorporation increased steeply after the last injection of HU and at 6 h a maximum value of 50% was obtained. Subsequently, the 3H-TdR index gradually decreased to 11% after 12 h. At 8, 15, and 30 days labeling indices of 1.9%, 0.5%, and 0.3% were determined. The mitotic index was highest with 0.21-0.22% between 12 and 16 h after removal of the HU block. The growth fraction amounted to 53%. The results reported here show a satisfactory degree of synchrony of stimulated urothelial proliferation obtained by multiple fractionated doses of HU. In particular the cystectomy model will be useful for testing possible cell cycle specificity of urothelial carcinogenesis.

The present study deals with the effect of stimulation of urothelial proliferation on experimental bladder carcinogenesis. To induce proliferative activity of the bladder mucosa cyclophosphamide (cp) was intraperitoneally administered to rats in a single dose (100 mg/kg). N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was used as carcinogen and administered by gavage in 3 fractionated doses when proliferation of the urothelium was highest at 28 and 40 hr as well as 7 days following the injection of cp. Contrary to our original working hypothesis, tumor development proved to be inhibited in the bladder following initial stimulation of urothelial proliferation by cp. After administration of a low total dose of BBN (300 mg/kg) and an experimental period of 6 and 12 months none of the rats pretreated with cp developed a tumor in the regenerating bladder, whereas solitary transitional cell papillomas were observed in 6.7% of the control animals with a quiescent bladder. Following administration of BBN at a high total dose (1.300 mg/kg) and an induction time of 4, 6 and 12 months papillomas and non-invasive papillary transitional cell carcinomas occurred in only 21.6% of the rats initially receiving cp but in 48.1% of the control animals without stimulation of urothelial proliferation by cp. After treatment with BBN alone there was a far larger number of rats with multiple tumors in the quiescent bladder. The reduction in the incidence of tumors following administration of cp is not attributable to a prolongation of the latency period or induction time. It is an open question which mechanisms are responsible for the observed inhibition of experimental bladder carcinogenesis. An increased DNA repair induced synchronously with the stimulated replicative de-novo DNA synthesis or a decreased activity of urothelial enzymes metabolizing BBN to its ultimate carcinogen are proposed as the most likely explanations.