High Yield Selective Induction of Uterine Endometrial Adenocarcinomas in CD-1 Mice by N-Ethyl-N'-nitro-N-nitrosoguanidine Combined with 17.BETA.-Estradiol.

Abstract

In order to assess a combined carcinogen and hormone protocol for selective induction of uterine adenocarcinomas in mice, 79 illumination-induced persistent estrous CD-1 mice, divided into four groups, were treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and/or 17β-estradiol (E2). Groups 1 and 3 were given a single intra-uterine administration of polyethylene glycol (PEG) at 10 weeks of age, while Groups 2 and 4 received ENNG (12.5 mg/kg), dissolved in PEG. Mice of Groups 3 and 4 were also implanted with E2 pellets s.c. one week earlier and the pellets were once renewed after 8 weeks. At 15 weeks after the ENNG treatment, the mice were killed for histopathological and endocrinological examination. All groups demonstrated endometrial proliferative lesions, although no severe hyperplasias or adenocarcinomas were found in the control group (Group 1). The incidences of adenocarcinomas in Groups 2, 3, and 4 were 6 (1/19), 25 (5/20), and 55% (11/20), respectively, those for Groups 3 and 4 being significant as compared to the lack in Group 1. The E2: progesterone (E2: P) ratios in Groups 3 and 4 were also significantly increased. These results indicate that an increased E2: P ratio is important for endometrial adenocarcinoma development in CD-1 mice, acting with or without chemical carcinogen initiation to cause uterine cancer development. The relatively short duration, and specifically high yield mean that the present protocol has advantages for two-stage uterine carcinogenicity studies in mice.