Inhibitory effects of estrogen and castration on the early stage of pancreatic carcinogenesis in Fischer rats treated with azaserine.

ABSTRACT

Effects of sex steroids on pancreatic carcinogenesis during the early stage were studied in azaserine-treated rats of both sexes. Fischer rats were given weekly i.p. injections of azaserine (30 mg/kg) [CAS115-02; diazoacetate serine(ester)] at 2 and 3 weeks of age and were divided into six groups. Castration, ovariectomy, and s.c. implantations of either a 0.3-mg or a 1.0-mg 17 beta-estradiol (CAS50-28.2; estradiol) pellet were performed at 7 weeks of age. The groups were as follows group 1, intact male; group 2, castrated; group 3, castrated plus 0.3 mg estradiol; group 4, castrated plus 1.0 mg estradiol; group 5, ovariectomized; and group 6, intact female. Rats were killed 4 months after the last injection of azaserine. Azaserine treatment induced atypical acinar cell foci and nodules (AACN) in both sexes. The acidophilic AACN are considered preneoplastic lesions. An apparent sex difference was observed; the number of acidophilic AACN was greater in male rats than in female rats. Castration caused a significant decrease in both the serum testosterone levels and the number of acidophilic AACN, which were comparable to those in ovariectomized female rats. Furthermore, when estradiol treatment was administered to the castrated male rats, a linear decrease in the number of acidophilic AACN and an elevation in the serum estradiol levels were observed and were dose dependent. There were also positive relationships between estradiol treatments and the mean pituitary and pancreas weights. These results showed that estradiol treatment and the drop in testosterone levels caused by castration were highly effective in inhibiting the development and growth of preneoplastic lesions of the pancreas of the rats treated with azaserine. This estradiol effect was dose dependent. The present study, therefore, provides evidence that estrogen may act as an inhibitor and androgen as a promoter in the early stage of pancreatic carcinogenesis in rats.