Tanaka T, Kawabata K, Kakumoto M, Makita H, Matsunaga K, Mori H, Satoh K, Hara A, Murakami A, Koshimizu K, Ohigashi H
Department of Pathology, Gifu University School of Medicine.
Jpn J Cancer Res. 1997 Sep;88(9):821-30. doi: 10.1111/j.1349-7006.1997.tb00457.x.
In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.
在我们寻找食品中具有化学预防功效的天然化合物的研究中，以偶氮甲烷（AOM）诱导的结肠异常隐窝灶和结肠黏膜细胞增殖作为生物标志物，发现泰国可食用植物高良姜中存在的一种黄嘌呤氧化酶抑制剂——乙酸1'-乙酰氧基胡椒酚酯（ACA）具有功效。本研究旨在测试在启动期或启动后期给大鼠喂食ACA时，其抑制AOM诱导的结肠癌发生的能力。雄性F344大鼠每周皮下注射3次AOM（15毫克/千克体重）以诱导结肠肿瘤。从首次给予AOM（启动期喂食）前一周开始，给它们喂食含100或500 ppm ACA的饲料4周。其他组从最后一次注射AOM后一周开始（启动后期喂食），喂食含ACA的饲料34周。在研究结束时（第38周），AOM诱导结肠腺癌的发生率为71%（12/17只大鼠）。启动期喂食ACA导致结肠癌发生率显著降低（100 ppm ACA喂食抑制54%，500 ppm ACA喂食抑制77%，P值分别为0.03和0.001）。启动后期喂食ACA也抑制了结肠癌的发生率（100 ppm ACA喂食抑制45%，500 ppm ACA喂食抑制93%，P值分别为0.06和0.00003）。这种抑制呈剂量依赖性，且与增殖生物标志物的抑制有关，如结肠黏膜中的鸟氨酸脱羧酶活性以及血液和结肠黏膜中的多胺含量。ACA还提高了肝脏和结肠中Ⅱ相酶谷胱甘肽S-转移酶（GST）和醌还原酶（QR）的活性。这些结果表明，ACA可通过抑制结肠黏膜中的细胞增殖以及诱导GST和QR来抑制AOM诱导的结肠癌发生。这些结果证实了我们之前的发现，即喂食ACA可有效抑制结肠异常隐窝灶的发展。这些发现提示了ACA对结肠癌发生可能具有化学预防能力。
