STUDIES ON THE MECHANISM OF UTERINE CARCINOGENESIS USING TWO-STAGE MOUSE CARCINOGENESIS PROTOCOL

两阶段小鼠致癌方案研究子宫癌变机制

• 批准号: 09670244
• 负责人: TAKAHASHI Masakazu
• 金额: $ 1.98万
• 依托单位: SASAKI INSTITUTE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670244/
• 关键词: Two-stage mouse uterine carcinogenesis method; Uterine adenocarsinomas; 17β-Estradiol; Mice; EィイD22ィエD2 metabolite-steroids; Tamoxifen; Ascorbic acid

In this studies, a two-stage mouse uterine carcinogenesis method by a initiator/N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and promoter/17β-estradiol (EィイD22ィエD2) was established, and also the effects of tamoxifen (TAM) and ascorbic acid (ASA) on endometrial adenocarcinoma development was investigated using this model, in addition to promotion effects of EィイD22ィエD2 and it's metabolite-steroids in. High incidence of adenocarcinomas was observed in ENNG combined with EィイD22ィエD2 group animals at the termination of the experiment (week 15 after the ENNG-treatment), but ENNG + EィイD22ィエD2 + TAM-treated group could not see any promotion effect. TAM decreased uterine weight compared with control. These results indicate that administration of TAM inhibit the promoting effect of EィイD22ィエD2 on ENNG-induced uterine carcinogenesis, TAM affecting as an anti-estrogen. On the other hand, incidence of adenocarcinomas in the ENNG + EィイD22ィエD2 + ASA group was 1.5 time higher than ASA-untreated group, but … More being not significant. It is known that administration of ascorbic acid (0.3% in drinking water) inhibit the promoting effect of estradiol dipropionate on uterine sarcoma development by 1,2-dimethylhydrazine in CBA mice. Thus, ASA inhibited promoting effect of EィイD22ィエD2 on uterine sarcoma development, but activated adenocarcinoma. This indicate, estrogen may have different promotion mechanism between uterine adenocarcinoma and sarcoma. Promotion effects of EィイD22ィエD2 and its metabolite-steroids on ENNG-initiated mice were examined. High incidences of adenocarcinoma were observed in mice treated with EィイD21ィエD2, EィイD22ィエD2 and 17-epi EィイD23ィエD2 steroids, medium incidences were observed in animals treated with EィイD23ィエD2, 16α-hydroxy and 16β-hydroxy EィイD21ィエD2 steroids. 2-Hydroxy and methoxy steroids did not affected. These results indicate that promotion effects of EィイD22ィエD2 metabolite-steroids on uterine carcinogenesis in ENNG-initiated mice were shown by metabolite products to 16α-OH and 16β-OH steroids, but not to 2β-OH steroids. Less

本研究建立了以N-乙基-N‘-硝基-N-亚硝基-N-亚硝基和17-β-雌二醇(E-ィイD22ィエD2)为启动子的两步法小鼠子宫内膜癌模型，并用此模型研究了三苯氧胺()和抗坏血酸(AsC)对小鼠子宫内膜腺癌发生的影响，以及E-ィイD22ィエD2及其代谢产物类固醇对子宫内膜腺癌发生的促进作用。实验结束时(实验结束后15周)，ENNG联合EィイD22ィエD2组动物的腺癌发生率较高，而ENNG+EィイD22ィエD2+治疗组未见明显的促腺癌作用。与对照组相比，组子宫重量减轻。以上结果表明，可抑制E-ィイD22-ィエ-D2对环磷酰胺所致小鼠子宫癌变的促进作用，而具有抗雌激素作用。另一方面，Enng+EィイD22ィエD2+AsA组的腺癌发生率是未治疗组的1.5倍，但…越多就越不重要。已知，饮水中0.3%的抗坏血酸可抑制二丙酸雌二醇对1，2-二甲基肼所致CBA小鼠子宫肉瘤生长的促进作用。因此，AsA抑制EィイD22ィエD2对子宫肉瘤生长的促进作用，但激活腺癌。提示雌激素在子宫腺癌和肉瘤中可能具有不同的促进机制。研究了E-ィイD22、ィエ-D2及其代谢物--类固醇对环磷酰胺诱导的小鼠免疫功能的促进作用。EィイD21ィエD2、EィイD22ィエD2和17-epi EィイD23ィエD2类固醇组小鼠腺癌发生率较高，EィイD23ィエD2、16α-羟基和16β-羟基EィイD21ィエD2类固醇组小鼠的腺癌发生率中等。2-羟基和甲氧基类固醇对其无影响。这些结果表明，EィイD22ィエD2代谢物对环磷酰胺诱发小鼠子宫癌变的促进作用是通过代谢产物16α-OH和16β-OH表现出来的，而对2β-OH类固醇的促进作用不明显。较少

项目成果

Katuda S.et al.: "Dose-and treatment duration-related effects of p-tert-octylphenol on female rats"Peprod.Toxicol., in press. 14. (2000)

Katuda S.等人：“对叔辛基苯酚对雌性大鼠的剂量和治疗持续时间相关影响”Peprod.Toxicol.，出版中。

Yoshida, M., Kudoh, K., Katsuda, S., Takahashi, M., Ando, J. and Maekawa, A.: "Inhibitory effects of uterine endometrial carcinogenesis in Donryu rats by tamoxifen"Cancer Lett.. 134. 43-51 (1998)

Yoshida, M.、Kudoh, K.、Katsuda, S.、Takahashi, M.、Ando, J. 和 Maekawa, A.：“他莫昔芬对 Donryu 大鼠子宫内膜癌变的抑制作用”Cancer Lett.. 134. 43

Katsuda, S., Yoshida, M., Watanabe, T., Kuroda, H., Ando-Lu, J., Takahashi, M., Hayashi, H. and Maekawa, A.: "Estrogen receptor mRNA in uteri of normal estrous cycling and ovariectomized rats by in situ hybridization"Proc. Soc. Exptl. Biol. Med.. 221. 207

Katsuda, S.、Yoshida, M.、Watanabe, T.、Kuroda, H.、Ando-Lu, J.、Takahashi, M.、Hayashi, H. 和 Maekawa, A.：“正常子宫中的雌激素受体 mRNA

Katsuda, s., et al.: "Estrogen receptor mRNA in uteri of normal eatrous cycling and ovariectomized rats by in situ hybridization"Proc. Soc. Exptl. Biol. Med.. 221. 207-214 (1999)

Katsuda, s., et al.：“通过原位杂交测定正常进食周期和卵巢切除大鼠子宫中的雌激素受体 mRNA”Proc。

Nishiyama, K., Ando-Lu, J., Nishimura, S., Takahashi, M., Yoshida, M., Sasahara, K., Miyajima, K. and Maekawa, A.: "Initiating and promoting effects of concurrent oral administration of ethylenethiourea and sodium nitrite on uterine endometrial adenocarci

Nishiyama, K.、Ando-Lu, J.、Nishimura, S.、Takahashi, M.、Yoshida, M.、Sasahara, K.、Miyajima, K. 和 Maekawa, A.：“同时口服的启动和促进作用