Promotion, but not progression, effects of tamoxifen on uterine carcinogenesis in mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine.
Effects of tamoxifen (TAM) on development of uterine endometrial carcinogenesis were studied in intact and ovariectomized (OVX) mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). In experiment I, animals were implanted with cholesterol (ChL, controls) or TAM (5% w/w) and/or 17beta-oestradiol (E(2), 0.5% w/w) pellets s.c. from 9 to 25 weeks of age, until the termination of the experiment, and all received a single intra-uterine administration of ENNG (12.5 mg/kg) at 10 weeks of age. They were divided into four groups: ENNG + ChL (control), ENNG + TAM, ENNG + E(2) and ENNG + TAM + E(2). Endometrial proliferative lesions (hyperplasias and/or carcinomas) were observed in all groups, the incidences in the TAM- and/or E(2)-treated groups being two times higher than in the ChL-treated control animals. High induction (11/20, 55%) of adenocarcinomas was observed in the E(2) group but this was significantly decreased in combination with TAM (2/20, 10%), no carcinomas being found in the TAM group. In experiment II, animals pre-treated with TAM (10 weeks) and receiving E(2) post-treated (4 weeks) developed adenocarcinomas, although no cancers were observed in mice treated by ChL instead of TAM. In animals pre-treated with TAM and post-treated with ChL or TAM, no adenocarcinomas were also developed. In OVX mice (experiment III), proliferative lesions were observed in the TAM- and/or E(2)-treated groups, at incidences significantly higher than in ChL-treated animals, in which these lesions were completely absent. However, no adenocarcinomas were found, only slight hyperplasias being observed in the TAM group, although the incidence of adenocarcinoma was highest in the E(2) alone group, and significantly decreased in combination with TAM, as in experiment I. These results indicate that TAM may itself exert promotion effects, while exhibiting an anti-progression influence on uterine carcinogenesis in adult mice initiated by ENNG and receiving E(2).
Takahashi
Masakazu
M
Department of Pathology, Sasaki Institute, 2-2 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. takahashi@sasaki.or.jp
Shimomoto
Takasumi
T
Miyajima
Katsuhiro
K
Iizuka
Seiichi
S
Watanabe
Takao
T
Yoshida
Midori
M
Kurokawa
Yuji
Y
Maekawa
Akihiko
A
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D004195:Disease Models, Animal; D004347:Drug Interactions; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D015994:Incidence; D008769:Methylnitronitrosoguanidine / Q000031:analogs & derivatives* / Q000633:toxicity*; D051379:Mice; D013629:Tamoxifen / Q000633:toxicity*; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000473:pathology
D002273:Carcinogens; D013629:Tamoxifen; D008769:Methylnitronitrosoguanidine; C013525:ENNG