Carcinogenicity of cyproterone acetate in the mouse.
The synthetic progestin cyproterone acetate (CPA) has been shown to be a hepatocarcinogen in the rat, but little is known of its effects in mice. A 52 week CPA study in the mouse strain C57Bl/10J has been reported not to produce liver tumours, although CPA induced significant liver enlargement and induction of the mixed function oxidase CYP3A. The present study is a further investigation of the effects of CPA in mice of the C57Bl/10J strain dosed for 104 weeks. A group of 40 mice/sex were fed 800 p.p.m. CPA in the diet for 104 weeks with a control group of eight/sex. Mortality was high in females after 40 weeks due to hormonal effects in the uterus; no female and only four CPA-dosed males survived to 104 weeks. Liver cell hypertrophy with increased fat and glycogen and single cell or small multifocal areas of hepatocellular necrosis were universal. Proliferating cell nuclear antigen demonstrated an increase in proliferating cells within tumours and within the non-tumour bearing liver of CPA-dosed mice compared with normal livers of control mice. Hepatocellular tumours developed in 44% of males and 22% of females dosed with CPA, compared with none in the controls (the strain has a low, <10%, incidence of spontaneous liver tumours compared with other mouse strains). In addition, over 85% of both sexes dosed with CPA developed adenomatous polyps of the pyloric antrum and pancreatic islet cell hyperplasia, shown by immunostaining to be chiefly of insulin-secreting cells. Adrenocortical atrophy was also observed with other widespread effects in the endocrine system. The results suggest that the liver tumours, as in the rat, are likely to be related to effects on liver growth and mitogenesis. It is suggested that the tumours of the stomach and the pancreatic islet cell hyperplasia are manifestations of the effects of CPA in the endocrine system.
Tucker
M J
MJ
Safety of Medicines Department, ZENECA Pharmaceuticals, Cheshire, UK.
Kalinowski
A E
AE
Orton
T C
TC
D018256:Adenomatous Polyps / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D017373:Cyproterone Acetate / Q000633:toxicity*; D005260:Female; D006965:Hyperplasia; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D012727:Sex Characteristics; D013045:Species Specificity; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology
D002273:Carcinogens; D017373:Cyproterone Acetate