IN 1952 Bonser, Clayson, Jull and Pyrah examined the carcinogenic action of 2-naphthylamine (I) and the hydrochloride of one of its metabolites, namely, 2-amino-1-naphthol (II), by means of the implantation of paraffin wax pellets containing the chemicals into the lumen of the mouse bladder. On the basis of experiments on forty-two mice they concluded that whereas the parent amine, 2-naphthylamine, was not active under these conditions the metabolite, 2-amino-1-naphthol was carcinogenic.The carcinogenicity of 2-amino-l-naphthol and the absence of such activity with 2-naphthylamine led Clayson (1953) to suggest that aromatic amines and certain other compounds were carcinogenic because of their conversion in the animal body to ortho hydroxy-amines. As a first step in testing this hypothesis it was necessary to show that ortho hydroxy-amines are in fact carcinogenic.It has recently been shown that 4-aminodiphenyl (para-xenylamine, VII) elicits biological responses similar to 2-naphthylamine. It is an industrial bladder OH OSO3H
IN 1951, Bonser, Clayson and Jull published some of the results of a quantitative study of the metabolism of 2-naphthylamine by various species. An apparent correlation was demonstrated between the proportion of a dose of 2-naphthylamine (I) excreted by way of the urine as 2-amino-1-naphthol derivatives (II) and the biological response of the species to treatment with 2-naphthylamine.Thus it was shown that the dog, which is particularly susceptible to 2-naph-thylamine carcinogenesis, excretes 55 to 70 per cent of a dose of 2-naphthylamine as 2-amino-1-naphthol conjugates, whereas the mouse, rat and rabbit, which are less susceptible, excrete smaller quantities in this form. Quantitative studies also revealed that the concentration of 2-amino-l-naphthol derivatives in the urine relative to the plasma was approximately 200:1 and from this it was concluded that the exposure of the urinary tract epithelium to the metabolite was very much greater than that of any other part of the body.Evidence was also presented (Bonser et al., 1951) that synthetic 2-amino-1-naphthol hydrochloride (III) was a carcinogen, using the method devised by Jull (1951)
MAMMARY carcinomas can be induced in virgin IF female mice by means of chemical carcinogens (Bonser, 1958). But it was shown by Bonser (1954) that oestrogen alone was not a sufficient substitute for the ovaries as the hormonal stimulus in the induction of such tumours by methylcholanthrene. However, by replacement of the ovarian steroid hormones by oestrogen and progesterone, Jull (1954) was able to obtain 9 tumours in 11 ovariectomised mice. He also demonstrated (1953) that virgin females of this strain have a well-developed duct and acinar system, the latter reaching a maximum at about 18 weeks of age but showing much individual variation. This extensive acinar development and the demonstration by van der Lee and Boot (1955) that spontaneous pseudopregnancy is frequent in virgins of some mouse strains when the females are caged in groups, suggested that high levels of progesterone might be operating in the IF female and might account for the high incidence of breast tumours induced by chemical carcinogens. It was therefore decided to test the effect of repeated induced pseudopregnancies on tumour induction by a chemical carcinogen.The strain chosen was the BALB/c, which does not carry the milk factor (Andervont, 1940) and has a low incidence of spontaneous mammary cancer. The only information available regarding the reaction of this strain to chemical carcinogens was that obtained by Squartini (1958) who had failed to induce mammary tumours in 30 virgin mice by means of subcutaneous injection of 1 mg.of 20-methylcholanthrene in 0.2 c.c. of olive oil. There was, therefore, no guide in regard to the dose and duration of the chemical treatment to be adopted. In order to gain an insight into the mode of action of the chemical, it was decided to test three groups of mice: virgins kept five in a cage; virgins deprived of the olfactory lobes and kept singly in order to reduce pseudopregnancy to a minimum (van der Lee and Boot, 1956); and virgins kept with vasectomised males in order to induce pseudopregnancy.
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