Absence of a Complete Carcinogenic Effect of Phenacetin on the Quiescent and Proliferating Urothelium Stimulated by Partial Cystectomy

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Abstract
Whether phenacetin (PH) exerts a complete solitary carcinogenic effect on the quiescent and rapidly proliferating urothelium of the lower urinary tract of the rat was tested. To stimulate proliferative activity, resection of 1/3 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 3 single doses when proliferative activity was highest. After an experimental period of 2 yr 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 fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla has to be considered not a true preneopalstic, 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. Most likely, a metabolite of PH realizes tumor growth only as cocarcinogen with initiation-stimulating and/or initiation-promotion effects acting together with other causative factors during multifactorial multistage carcinogenesis. Based on the 4 experimental findings, the concept of PH as a solitary complete urothelial carcinogen for man should be reassessed.

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