Correlation Between the Chemical Induction of Hyperplasia and of Malignancy in the Bladder Epithelium

Abstract

4-ETHYLSULPHONYLNAPHTHALENE-1 -SULPHONAMIDE (HPA) induces hyperplasia of the bladder epithelium in the rat and mouse (Paget, 1958;Sen Gupta, 1962). The hyperplasia arises within forty-eight hours of the first administration of the chemical (Bonser and Clayson, 1964) and with repeated dosing is still present after forty weeks (Sen Gupta, 1962). Carcinomas of the bladder were found in Ab x IF mice receiving the chemical for up to sixty-five weeks and were more prevalent in female than in male mice (Bonser and Clayson, 1964).The discovery of the carcinogenic action of HPA on mouse bladder epithelium was unusual in so far as the tests were undertaken following observation of the induction of hyperplasia. Other bladder carcinogens were found, more or less by chance, as a result of their action over long periods in man or experimental animals and their early effects have largely been ignored. The present report is an attempt to remedy this omission.Relatively few chemicals are known to induce bladder cancer in the experimental animal (Boyland, 1963). In some cases the absence of tumours may have been due to a failure to examine this organ with sufficient care. Therefore some hitherto unpublished long term tests in which the bladder has been adequately examined, are included in this paper in order to strengthen the comparison between the early effects of a chemical and the formation of tumours. MATERIALS AND METHODS Mice

Early Effects of Cyclophosphamide on Mouse Bladder Epithelium

“…As for the possible carcinogenic effect of cyclophosphamide on bladder epithelium [11], this does not seem likely in mice considering the assump tion by Clayson et al [5] that a correlation exists between early hyper plasia and the ultimate development of malignancy. On the other hand, while T okuoka [19] has reported a higher incidence of tumours in mice following repeated injections of cyclophosphamide, no bladder tumour has been detected and this drug has not resulted in a bladder carcinogen in C57 x IF mice, either alone or associated to paraffin wax-pellet im plantation [3].…”

The influence of a foreign body on the induction of tumours in the bladder epithelium of the mouse.

“…Such a mechanism is made more probable by the demonstration by Walker (1959) that wounding the bladder epithelium of the mouse with a pointed scalpel blade is followed by a wave of mitotic activity from one to four days thereafter. In other, unpublished, observations it has been found that the hyperplasia induced by the oral administration of chemical bladder carcinogens (Clayson et al, 1965) is also associated with an increase in the number of mitoses in the epithelium.…”

“…implicated as a relevant factor in the induction of cancer of the bladder of mice given chemicals by mouth (Clayson, Lawson, Santana and Bonser, 1965). The technique of bladder implantation has been used to test chemicals for local carcinogenic action (Jull, 1951;Allen, Boyland, Dukes, Horning and Watson, 1957).…”

Further investigations on the proliferative response of mouse bladder epithelium to 4-ethyl-sulphonylnaphthalene-1-sulphonamide.

“…It is possible that the A x IF mice are intrinsically less sensitive to ENS but, alternatively, the low incidence of bladder tumours may be a result of the condition of many of the mice during the experiment. This opinion is reinforced by the fact that the Ab x IF mice used by Clayson and Bonser (1965) developed a higher incidence of bladder tumours despite the Ab parents being derived by Caeserian section from an A mouse of the line used in this experiment.…”

“…Bladder tumours result from prolonged feeding of ENS to mice (Clayson and Bonser, 1965;Clayson, Pringle and Bonser, 1967). Hyperplasia is more severe and tumcours are more frequent in female than in male mice.…”