N-methyl-N-nitrosourea (MNU), methyl methane sulphonate (MMS), ethyl methane sulphonate (EMS) and cyclophosphamide (CP) are all cytotoxic to the transitional epithelium lining the urinary bladder, and also cause haemorrhage from the subepithelial blood capillaries. Erythrocytes enter the epithelium and are phagocytosed by the epithelial cells where they are subsequently digested. Two other compounds, dibutyl nitrosamine (DBN) and N-(4-(5-nitro-2-furyl)-2-thiazolyl)-formamide (NFTF) are only mildly cytotoxic but produce bladder epithelial tumours. Where haemorrhage occurs in these tumours, the erythrocytes are phagocytosed and digested by the neoplastic epithelial cells.
The ingested red cells appear to lie free in the epithelial cell cytoplasm, surrounded by only a single unit membrane. Densitometric tracings, however, show that this membrane is derived from the epithelial cells and that the red cells lie within a phagocytic vacuole. Careful inspection reveals the red cell membrane within the dense content of the vacuole, indicating that the permeability of the red cell membrane changes rapidly as soon as it is engulfed, so that haemoglobin is released into the phagocytic vacuole. The contents of the vacuole disintegrate and myelin figures and small amounts of residual dense material appear, but at no time was it possible to demonstrate acid phosphatase activity associated with the vacuole.