Kawamori T, Tanaka T, Hara A, Yamahara J, Mori H
First Department of Pathology, Gifu University School of Medicine, Japan.
Cancer Res. 1995 Mar 15;55(6):1277-82.
Modifying effects of dietary exposure of seven naturally occurring products on the development of colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM) were investigated in male F344 rats. The effects of these compounds on proliferation biomarkers such as the number of silver-stained nucleolar organizer region protein, ornithine decarboxylase activity, and polyamine concentration in the colon were also estimated. The naturally occurring products tested included four terpenoids (rebaudioside A, oleanolic acid, costunolide, and soyasaponin A2), one flavonoid (liquiritin), and two isocoumarins (phyllodulcin and hydrangenol). Animals were given 3 weekly s.c. injections of AOM (15 mg/kg body weight) to induce ACF. These rats were fed the diet containing 200 ppm of each test chemical for 5 weeks, starting 1 week before the first dosing of AOM. All rats were sacrificed 2 weeks after the last AOM injection to estimate their modulatory effects on the occurrence of ACF and the cell proliferation biomarkers in the colon. In groups of rats given AOM and hydrangenol, oleanolic acid, or costunolide, the frequencies of ACF/colon were significantly lower than that of AOM alone (P < 0.05, P < 0.005, and P < 0.05, respectively). In groups of rats given AOM and costunolide and those treated with AOM and soyasaponin A2, both ornithine decarboxylase activity and polyamine concentration of the colonic mucosal tissue were significantly decreased compared with those in rats given AOM alone (P < 0.05 and P < 0.001 for costunolide and P < 0.001 and P < 0.05 for soyasaponin A2, respectively). In groups of rats given AOM and liquiritin, oleanolic acid, or costunolide, the numbers of silver-stained nucleolar organizer regions/nucleus were significantly lower than that of AOM alone (P < 0.05, P < 0.01, and P < 0.05, respectively). Costunolide decreased four AOM-induced biomarkers, such as the frequencies of ACF/colon, ornithine decarboxylase activity, polyamine concentration level, and silver-stained nucleolar organizer region number in the colon. These results indicate that, among the test chemicals, costunolide has blocking effects against rat colon carcinogenesis and is a possible chemopreventive agent against colon tumorigenesis. Also, the short-term model described here could be a very useful prescreening tool for chemopreventive agents against colon cancer.
在雄性F344大鼠中研究了七种天然产物的饮食暴露对由氧化偶氮甲烷（AOM）诱导的结肠异常隐窝灶（ACF）发展的影响。还评估了这些化合物对增殖生物标志物的影响，如结肠中银染核仁组织区蛋白的数量、鸟氨酸脱羧酶活性和多胺浓度。测试的天然产物包括四种萜类化合物（甜菊糖苷A、齐墩果酸、木香烯内酯和大豆皂苷A2）、一种黄酮类化合物（甘草苷）和两种异香豆素（卫矛醇和氢化花椒毒素）。给动物每周皮下注射3次AOM（15mg/kg体重）以诱导ACF。从首次给予AOM前1周开始，这些大鼠喂食含有200ppm每种测试化学品的饮食5周。在最后一次注射AOM后2周处死所有大鼠，以评估它们对结肠中ACF发生和细胞增殖生物标志物的调节作用。在给予AOM和氢化花椒毒素、齐墩果酸或木香烯内酯的大鼠组中，ACF/结肠的频率显著低于单独给予AOM的组（分别为P<0.05、P<0.005和P<0.05）。在给予AOM和木香烯内酯的大鼠组以及用AOM和大豆皂苷A2处理的大鼠组中，与单独给予AOM的大鼠相比，结肠黏膜组织的鸟氨酸脱羧酶活性和多胺浓度均显著降低（木香烯内酯分别为P<0.05和P<0.001，大豆皂苷A2分别为P<0.001和P<0.05）。在给予AOM和甘草苷、齐墩果酸或木香烯内酯的大鼠组中，银染核仁组织区/细胞核的数量显著低于单独给予AOM的组（分别为P<0.05、P<0.01和P<0.05）。木香烯内酯降低了四种AOM诱导的生物标志物，如ACF/结肠的频率、鸟氨酸脱羧酶活性、多胺浓度水平和结肠中银染核仁组织区的数量。这些结果表明，在测试化学品中，木香烯内酯对大鼠结肠癌发生具有阻断作用，是一种可能的预防结肠癌发生的化学预防剂。此外，这里描述的短期模型可能是一种非常有用的针对结肠癌化学预防剂的预筛选工具。
