Cell kinetics of mouse urinary bladder epithelium. V. Changes in the proportion of cells with various nuclear DNA content after repeated doses of cyclophosphamide.

A dose of 2 mg cyclophosphamide (Sendoxan, "Pharamcia", Sweden) dissolved in 0.2 ml distilled water was injected intraperitoneally once a week to 12 hairless mice for three months. Four animals were killed at 1, 2 and 3 months and micro-flow fluormetric histograms of the bladder epithelial cells were made. The proportion of cells in diploid S phase remained normal at 1 and 2 months, but increased at 3 months. The proportion of tetraploid S-phase cells fell rapidly and markedly and there were almost no cells in this phase at 1, 2 and 3 months. The proportion of diploid cells increased, the proportion of tetraploids was significantly reduced and the octoploid cells disappeared after 2 months. The changes are similar to those seen after repeated injections of the bladder carcinogen dibutylnitrosamine, but less pronounced. Since cyclophosphamide is a strong alkylating agent it is possible that, in the doses used, it is also a weak carcinogen for hte bladder epithelium. This must be tested in direct, long-term treatment experiments. Bladder cancers in humans receiving cyclophosphamide therapy have been described.