姜茶素对DMH诱导的大鼠大肠癌的化学预防作用研究
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摘要
北景／目的
姜茶素是由天然植物活性成分姜黄素和儿茶素组成的，这两种成分副作用极小，几乎无毒性作用。研究证实姜黄素、儿茶素单独应用对肿瘤的的发生都有一定的预防作用，但是两者联合应用是否有协同抑制大肠癌发生的作用，目前国内外尚无这方面的研究报道。大肠异常隐窝病灶(aberrant crypt foli，ACF)是比较理想的大肠癌中间生物学评价指标之一，而环氧化酶(Cyclooxygenase-2，COX-2)和过氧化物酶体增殖物激活受体γ(Peroxisome Proliferator-Activated Receptorγ，PPARγ)则是与恶性肿瘤细胞的生长和生存密切相关的两个药物作用的分子靶点。本实验首次将由儿茶素和姜黄素组成的姜茶素应用于二甲基肼(DMH)诱导的大鼠大肠癌的化学预防研究，旨在初步阐明以下几个方面的问题：
1．探讨姜茶素对DMH诱导的大鼠ACF形成及大肠癌的化学预防作用，评价姜茶素对大肠癌的化学预防作用效果。
2．探讨姜茶素对大鼠大肠癌细胞的增殖及凋亡有何影响，从细胞动力学及凋亡方面初步阐明其抑制肿瘤的机理。
3．探讨姜茶素对DMH诱导的大鼠大肠癌变过程中COX-2和PPARγ表达的影响，以期能从分子水平上初步阐明姜黄素和儿茶素联合应用抑制肿瘤的机理。
方法
1．利用DMH诱导大鼠大肠癌模型，实验大鼠分5个组：(1)阴性对照组；(2)阳性对照组(DMH组)；(3)姜黄素预防组(DMH+0.2％姜黄素)；(4)儿茶素预防组(DMH+0.2％儿茶素)；(5)姜茶素预防组(DMH+0.2％姜黄素+0.2％儿茶素)，其中阴性对照组20只，其它四组各30只。观察各预防药物对诱癌后第12W大鼠大肠ACF数量、第32W大鼠大肠癌的发生率、肿瘤抑制率、大鼠体积及分化程度的影响。应用美蓝染色法观察ACF的数量，HE染色法进行形态学观察和病理定性分析。
2．利用细胞增殖核抗原(PCNA)表示细胞增殖活性，利用细胞原
位末端标记技术(Tunel)检测细胞凋亡情况，观察姜茶素、儿茶素和姜
黄素对大鼠大肠癌细胞增殖和凋亡的影响。
.3.利用免疫组织化学方法、RT一pCR和免疫印迹(Westemblotting)
方法分别检测诱癌12w时大鼠大肠粘膜组织和32W时大鼠大肠癌组织
COX一2及PPARY表达的变化，并对这些指标的变化进行定性和定量分
析。
结果
1.姜茶素对DMH诱导的大鼠ACF数量的影响实验第12周时除
阴性对照组外，阳性对照组及3个药物预防组均有ACF形成。姜茶素、
姜黄素和儿茶素组大鼠大肠ACF的平均数量明显低于阳性对照组
(尸<0.01)。姜茶素组大鼠大肠AcF的平均数量和由3个以上异常隐窝
构成的AcF的平均数量低于姜黄素组、儿茶素组(P<0.05)，而姜黄素和
儿茶素单独应用组间相比差异无显著性。
2.姜茶素对DMH诱导大鼠大肠癌的影响实验第32周时除阴性
对照组外，阳性对照组、姜黄素、儿茶素和姜茶素预防组均诱导出大肠
癌，诱癌率分别为81.巧%、61.11%、58.82%和38.89%，3组药物都能降
低大鼠大肠癌的发生率，其中姜茶素组大肠癌发生率明显低于阳性对照
组(P<。.05)。姜茶素组大肠癌的抑制率(52.15%)高于姜黄素组(24.79%)
和儿茶素组(27.61%)(P<0.05)。研究
还发现姜茶素组大肠癌的平均数量和平均体积均最低，与阳性对照组相
比差异有显著性(尸<0.05)。无论是姜黄素、儿茶素还是姜茶素对大肠癌
的分化程度均无明显影响。
3.姜茶素对大肠癌细胞增殖指数、凋亡指数的影响与阳性对照组
相比3个药物预防组大鼠大肠癌组织的增殖指数明显降低(尸<0.05)、凋
亡指数明显增高(尸<0.05)，其中姜茶素组的作用效果最强。
4.姜茶素对COX一2表达的影响DMH可以诱导12w大鼠大肠粘
膜组织和32W大鼠大肠癌组织COX一2 mRNA和蛋白的表达。RT一PCR结
果显示:各组均可见COX一2 mRNA的扩增条带，阴性对照组的扩增带明
显弱于其它组;诱癌12w时，3个药物预防组都能抑制COX一2 mRNA
的表达，与姜黄素、儿茶素组相比，姜茶素组的抑制作用最强(尸<0.05);
实验32W时阳性对照组及3个预防药物组大肠癌组织COX一2 mRNA的
表达量明显升高，但各组间差异不明显。westem blotring方法检测了
COX一2蛋白的表达情况，结果显示:COX一2蛋白的表达与COX一2 mRNA
的表达情况基本一致，但阴性对照组无COX一2蛋白的表达。
5.姜茶素对Pp月卿表达的影响免疫组化结果显示:无论是诱癌
12w的大肠粘膜组织还是诱癌32w的大肠癌组织均有PPAR丫表达。
RT一PcR结果显示:1 Zw时各组大鼠大肠粘膜PPA砌InRNA的表达无显
著差异(P>0.OS);实验32W阳性对照组及3个预防药物组大肠癌组织
PPARy 1llRNA的表达明显高于阴性对照组(P<0.05)，但阳性对照组与
3个预防药物组间差异不明显。westem bfotting结果显示PPARY蛋白的表
达与PPA砌mRNA的表达基本一致。
结论
1.姜茶素、姜黄素和儿茶素均能抑制大鼠诱癌早期ACF的数量，对
DMH诱导的大鼠大肠癌有明显的化学预防作用。姜黄素和儿茶素联合应
用对大肠癌的发生有协同预防作用，这种协同预防作用有可能是通过协
同抑制ACF的形成实现的。
2.姜茶素、姜黄素和儿茶素能够抑制大鼠大肠癌细胞的增殖，诱导
大肠癌细胞的凋亡，其中姜
Background/Objectives
Jiangchasu is composed of curcumin and catechins, both of which are naturally plant active components and have nearly no adverse effects. It has been proved that both curcumin and catechins posses widespread anticancer properties. Now aberrant crypt foli (ACF) has been proposed as a good intermediate biomarker in colorectal cancer. Cyclooxygenase 2 (COX-2) and peroxisome proliferator-activated receptor gamma (PPARy) have emerged as promising candidate molecular targets for colorectal cancer. The thesis aimed to evaluate whether a combination of curcumin and catechins shows synergistic effects for cancer-preventive activity for rat colorectal cancer induced by dimethylhydrazine (DMH). It is focused on questions as follows.
1. To observe the inhibition effects of Jiangchasu on the number of
colon ACF and colorectal cancer induced by DMH on Wistar rats.
2. To evaluate the effects of Jiangchasu, curcumin and catechins on the cell proliferation and apoptosis of rat colorectal cancer were investigated, which was helpful to elucidate the anticancer mechanism of Jiangchasu.
3. To detect the effects of Jiangchasu, curcumin and catechins on expression of COX-2 and PPARy in DMH induced rat colorectal cancer, hoping to elucidate the chemoprevention mechanisms of Jiangchasu in molecular levels.
Methods
I. Wistar rat colorectal cancer was induced by DMH. All rats were randomly divided into five groups: (1) negative group: standardized food. (2) DMH group: standardized food + DMH. (3) curcumin group: standardized food with 0.2% curcumin + DMH. (4) catechins group: standardized food with 0.2% catechins + DMH. (5) Jiangchasu group: standardized food with 0.2% (curcumin and catechins) + DMH. The number of rat colorectal ACFs was observed by methylene blue staining. The incidence, number and size of
colorectal cancer were accounted. The changes of rat colorectal tissues in morphology were observed through hematoxylin-eosin (HE) staining.
2. Proliferation index displayed by PCNA through immunohischemistry and apoptosis index revealed by TUNEL are used to evaluate the chemoprevention effects of curcumin, catechins and Jiangchasu in rat colorectal cancer induced by DMH .
3. The expression of COX-2 and PPAR y in tissues of rats colorectal mucosa at 12W and in tissues of rats colorectal cancer at 32W after first DMH administration were examined with immunohistochemical staining, RT-PCR and Western blotting methods.
Results
1. The effects of Jiangchasu on the number of ACF At 12 weeks after the first administration, rats belong to groups 2-5 developed ACF. The dietary administration of Jiangchasu, curcumin and catechins caused significantly inhibition in the ACF incidence than that of in DMH treatment group (P<0.01). The inhibition effect of Jiangchasu group was the highest among three chemopreventive groups (P<0.05). There was no difference between curcumin and catechins group.
2. The effects of Jiangchasu on colorectal cancer At 32 weeks after the first administration, the incidence of the colorectal cancer were 81.15%, 61.11%, 58.82% and 38.89% in DMH, curcumin, catechins and Jiangchasu group respectively. The incidence of colorectal cancer in Jiangchasu group was significantly lower than that of in DMH group (P<0.05). The average numbers and volumes of rumors were significantly decreased in Jiangchasu group than that of in curcumin or cathchins group administration alone. All preventive drugs had no effects on the differentiation of cancer.
3. The effects of Jiangchasu on cell proliferation index and apoptosis index Compared with DMH group, proliferation index in preventive group was markedly decreased and apoptosis index was obviously increased. The effects of Jiangchasu group were significantly higher than that of the other groups.
4. The effects of Jiangchasu on expression of COX-2 DMH could
induce the expression of COX-2 in colon mucosa tissues at 12W and in colorectal cancer tissues at 32W. The results of RT-PCR showed
姜茶素是由天然植物活性成分姜黄素和儿茶素组成的，这两种成分副作用极小，几乎无毒性作用。研究证实姜黄素、儿茶素单独应用对肿瘤的的发生都有一定的预防作用，但是两者联合应用是否有协同抑制大肠癌发生的作用，目前国内外尚无这方面的研究报道。大肠异常隐窝病灶(aberrant crypt foli，ACF)是比较理想的大肠癌中间生物学评价指标之一，而环氧化酶(Cyclooxygenase-2，COX-2)和过氧化物酶体增殖物激活受体γ(Peroxisome Proliferator-Activated Receptorγ，PPARγ)则是与恶性肿瘤细胞的生长和生存密切相关的两个药物作用的分子靶点。本实验首次将由儿茶素和姜黄素组成的姜茶素应用于二甲基肼(DMH)诱导的大鼠大肠癌的化学预防研究，旨在初步阐明以下几个方面的问题：
1．探讨姜茶素对DMH诱导的大鼠ACF形成及大肠癌的化学预防作用，评价姜茶素对大肠癌的化学预防作用效果。
2．探讨姜茶素对大鼠大肠癌细胞的增殖及凋亡有何影响，从细胞动力学及凋亡方面初步阐明其抑制肿瘤的机理。
3．探讨姜茶素对DMH诱导的大鼠大肠癌变过程中COX-2和PPARγ表达的影响，以期能从分子水平上初步阐明姜黄素和儿茶素联合应用抑制肿瘤的机理。
方法
1．利用DMH诱导大鼠大肠癌模型，实验大鼠分5个组：(1)阴性对照组；(2)阳性对照组(DMH组)；(3)姜黄素预防组(DMH+0.2％姜黄素)；(4)儿茶素预防组(DMH+0.2％儿茶素)；(5)姜茶素预防组(DMH+0.2％姜黄素+0.2％儿茶素)，其中阴性对照组20只，其它四组各30只。观察各预防药物对诱癌后第12W大鼠大肠ACF数量、第32W大鼠大肠癌的发生率、肿瘤抑制率、大鼠体积及分化程度的影响。应用美蓝染色法观察ACF的数量，HE染色法进行形态学观察和病理定性分析。
2．利用细胞增殖核抗原(PCNA)表示细胞增殖活性，利用细胞原
位末端标记技术(Tunel)检测细胞凋亡情况，观察姜茶素、儿茶素和姜
黄素对大鼠大肠癌细胞增殖和凋亡的影响。
.3.利用免疫组织化学方法、RT一pCR和免疫印迹(Westemblotting)
方法分别检测诱癌12w时大鼠大肠粘膜组织和32W时大鼠大肠癌组织
COX一2及PPARY表达的变化，并对这些指标的变化进行定性和定量分
析。
结果
1.姜茶素对DMH诱导的大鼠ACF数量的影响实验第12周时除
阴性对照组外，阳性对照组及3个药物预防组均有ACF形成。姜茶素、
姜黄素和儿茶素组大鼠大肠ACF的平均数量明显低于阳性对照组
(尸<0.01)。姜茶素组大鼠大肠AcF的平均数量和由3个以上异常隐窝
构成的AcF的平均数量低于姜黄素组、儿茶素组(P<0.05)，而姜黄素和
儿茶素单独应用组间相比差异无显著性。
2.姜茶素对DMH诱导大鼠大肠癌的影响实验第32周时除阴性
对照组外，阳性对照组、姜黄素、儿茶素和姜茶素预防组均诱导出大肠
癌，诱癌率分别为81.巧%、61.11%、58.82%和38.89%，3组药物都能降
低大鼠大肠癌的发生率，其中姜茶素组大肠癌发生率明显低于阳性对照
组(P<。.05)。姜茶素组大肠癌的抑制率(52.15%)高于姜黄素组(24.79%)
和儿茶素组(27.61%)(P<0.05)。研究
还发现姜茶素组大肠癌的平均数量和平均体积均最低，与阳性对照组相
比差异有显著性(尸<0.05)。无论是姜黄素、儿茶素还是姜茶素对大肠癌
的分化程度均无明显影响。
3.姜茶素对大肠癌细胞增殖指数、凋亡指数的影响与阳性对照组
相比3个药物预防组大鼠大肠癌组织的增殖指数明显降低(尸<0.05)、凋
亡指数明显增高(尸<0.05)，其中姜茶素组的作用效果最强。
4.姜茶素对COX一2表达的影响DMH可以诱导12w大鼠大肠粘
膜组织和32W大鼠大肠癌组织COX一2 mRNA和蛋白的表达。RT一PCR结
果显示:各组均可见COX一2 mRNA的扩增条带，阴性对照组的扩增带明
显弱于其它组;诱癌12w时，3个药物预防组都能抑制COX一2 mRNA
的表达，与姜黄素、儿茶素组相比，姜茶素组的抑制作用最强(尸<0.05);
实验32W时阳性对照组及3个预防药物组大肠癌组织COX一2 mRNA的
表达量明显升高，但各组间差异不明显。westem blotring方法检测了
COX一2蛋白的表达情况，结果显示:COX一2蛋白的表达与COX一2 mRNA
的表达情况基本一致，但阴性对照组无COX一2蛋白的表达。
5.姜茶素对Pp月卿表达的影响免疫组化结果显示:无论是诱癌
12w的大肠粘膜组织还是诱癌32w的大肠癌组织均有PPAR丫表达。
RT一PcR结果显示:1 Zw时各组大鼠大肠粘膜PPA砌InRNA的表达无显
著差异(P>0.OS);实验32W阳性对照组及3个预防药物组大肠癌组织
PPARy 1llRNA的表达明显高于阴性对照组(P<0.05)，但阳性对照组与
3个预防药物组间差异不明显。westem bfotting结果显示PPARY蛋白的表
达与PPA砌mRNA的表达基本一致。
结论
1.姜茶素、姜黄素和儿茶素均能抑制大鼠诱癌早期ACF的数量，对
DMH诱导的大鼠大肠癌有明显的化学预防作用。姜黄素和儿茶素联合应
用对大肠癌的发生有协同预防作用，这种协同预防作用有可能是通过协
同抑制ACF的形成实现的。
2.姜茶素、姜黄素和儿茶素能够抑制大鼠大肠癌细胞的增殖，诱导
大肠癌细胞的凋亡，其中姜
Background/Objectives
Jiangchasu is composed of curcumin and catechins, both of which are naturally plant active components and have nearly no adverse effects. It has been proved that both curcumin and catechins posses widespread anticancer properties. Now aberrant crypt foli (ACF) has been proposed as a good intermediate biomarker in colorectal cancer. Cyclooxygenase 2 (COX-2) and peroxisome proliferator-activated receptor gamma (PPARy) have emerged as promising candidate molecular targets for colorectal cancer. The thesis aimed to evaluate whether a combination of curcumin and catechins shows synergistic effects for cancer-preventive activity for rat colorectal cancer induced by dimethylhydrazine (DMH). It is focused on questions as follows.
1. To observe the inhibition effects of Jiangchasu on the number of
colon ACF and colorectal cancer induced by DMH on Wistar rats.
2. To evaluate the effects of Jiangchasu, curcumin and catechins on the cell proliferation and apoptosis of rat colorectal cancer were investigated, which was helpful to elucidate the anticancer mechanism of Jiangchasu.
3. To detect the effects of Jiangchasu, curcumin and catechins on expression of COX-2 and PPARy in DMH induced rat colorectal cancer, hoping to elucidate the chemoprevention mechanisms of Jiangchasu in molecular levels.
Methods
I. Wistar rat colorectal cancer was induced by DMH. All rats were randomly divided into five groups: (1) negative group: standardized food. (2) DMH group: standardized food + DMH. (3) curcumin group: standardized food with 0.2% curcumin + DMH. (4) catechins group: standardized food with 0.2% catechins + DMH. (5) Jiangchasu group: standardized food with 0.2% (curcumin and catechins) + DMH. The number of rat colorectal ACFs was observed by methylene blue staining. The incidence, number and size of
colorectal cancer were accounted. The changes of rat colorectal tissues in morphology were observed through hematoxylin-eosin (HE) staining.
2. Proliferation index displayed by PCNA through immunohischemistry and apoptosis index revealed by TUNEL are used to evaluate the chemoprevention effects of curcumin, catechins and Jiangchasu in rat colorectal cancer induced by DMH .
3. The expression of COX-2 and PPAR y in tissues of rats colorectal mucosa at 12W and in tissues of rats colorectal cancer at 32W after first DMH administration were examined with immunohistochemical staining, RT-PCR and Western blotting methods.
Results
1. The effects of Jiangchasu on the number of ACF At 12 weeks after the first administration, rats belong to groups 2-5 developed ACF. The dietary administration of Jiangchasu, curcumin and catechins caused significantly inhibition in the ACF incidence than that of in DMH treatment group (P<0.01). The inhibition effect of Jiangchasu group was the highest among three chemopreventive groups (P<0.05). There was no difference between curcumin and catechins group.
2. The effects of Jiangchasu on colorectal cancer At 32 weeks after the first administration, the incidence of the colorectal cancer were 81.15%, 61.11%, 58.82% and 38.89% in DMH, curcumin, catechins and Jiangchasu group respectively. The incidence of colorectal cancer in Jiangchasu group was significantly lower than that of in DMH group (P<0.05). The average numbers and volumes of rumors were significantly decreased in Jiangchasu group than that of in curcumin or cathchins group administration alone. All preventive drugs had no effects on the differentiation of cancer.
3. The effects of Jiangchasu on cell proliferation index and apoptosis index Compared with DMH group, proliferation index in preventive group was markedly decreased and apoptosis index was obviously increased. The effects of Jiangchasu group were significantly higher than that of the other groups.
4. The effects of Jiangchasu on expression of COX-2 DMH could
induce the expression of COX-2 in colon mucosa tissues at 12W and in colorectal cancer tissues at 32W. The results of RT-PCR showed
引文
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5． Janne PA, Mayer RJ. Chemoprevention of colorectal cancer.N Engl J Med. 2000; 342 (26) : 1960-8
6． Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemoprevention.Ann N Y Acad Sci. 999;889:1-13
7． Badawi AF, Badr MZ. Chemoprevention of breast cancer by targeting cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma. Int J Oncol. 2002;20(6) :1109-1122
8． Spom MB, Suh N.Chemoprevention of cancer.Carcinogenesis. 2000;21(3) :525-30
9． Wargovich MJ. Colon cancer chemoprevention with ginseng and other botanicals.J Korean Med Sci. 2001; 16 Suppl:S81-86
10. Kossoy G, Ben-Hur H, Stark A, et al. Effects of a 15％ orange-pulp diet on tumorigenesis and immune response in rats with colon tumors. Oncol Rep. 2001;8(6):1387-1391
11. Gee JM, Noteborn HP, Polley AC, Johnson IT. Increased induction of aberrant crypt foci by 1,2-dimethylhydrazine in rats fed diets containing purified genistein or genistein-rich soya protein. Carcinogenesis. 2000; 21(12):2255-2259
12. Mahmoud NN, Carothers AM, Grunberger D, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.Carcinogenesis. 2000;21(5):921-927
13. Reddy BS, Hirose Y, Cohen LA, et al. Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention.Cancer Res. 2000; 60(17):4792-4797
14. Dai W, Liu T, Wang Q, et al.Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors.Int J Oncol. 2002;20(1): 121-126
15. Chen H, Zhang ZS, Zhang YL, Zhou DY. Curcumin inhibits cell proliferation by interfering with the cell cycle and inducing apoptosis in colon carcinoma cells. Anticancer Res 1999;19(5A):3675-3680
16．陈宏，张振书，张亚历，等．姜黄素诱导Lovo细胞凋亡．中国中医基础医学杂志 1999．03．28；5(3)：32-34
17．陈宏，张振书，姜泊，等．中药姜黄素抗癌作用及其机制研究．中华流行病学杂志 1998．09．10；19(5-B)：328-329
18．周京旭，张振书，杨希山，等．食用含姜黄素饲料抑制人鼠实验性肝癌。中华预防医学杂志 2002；1．36(5)：360
19. Cerhan JR, Putnam SD, Bianchi GD, et al. Tea consumption and risk of cancer of the colon and rectum. Nutr Cancer. 2001;41(1-2):33-40
20． Naasani I, Oh-Hashi F, Oh-Hara T, et al. Blocking telomerase by dietary polyphenols is a major mechanism for limiting the growth of human cancer cells in vitro and in vivo.Cancer Res. 2003;63(4) :824-830
21． Uesato S, Kitagawa Y, Kamishimoto M, et al. Inhibition of green tea catechins against the growth of cancerous human colon and hepatic epithelial cells.Cancer Lett. 2001;170(1) :41-44
22． Murakami C, Hirakawa Y, Inui H, Nakano Y, Yoshida H. Effect of tea catechins on cellular lipid peroxidation and cytotoxiciry in HepG2 cells.Biosci Biotechnol Biochem. 2002;66(7) : 1559-62
23． Tan X, Zhang Y, Jiang B, et al.Changes in ceramide levels upon catechins-induced apoptosis in LoVo cells. Life Sci 2002;70(17) :2023-2029
24． Tan X, Hu D, Li S, et al. Differences of four catechins in cell cycle arrest and induction of apoptosis in LoVo cells. Cancer Lett 2000; 158(1) : 1-6
25． Borrelli F, Mereto E, Capasso F, et al. Effect of bisacodyl and cascara on growth of aberrant crypt foci and malignant tumors in the rat colon.Life Sci. 2001;69(16) :1871-1877
26． Venkatesan N, Punithavathi D, Arumugam V. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol. 2000; 129(2) :231-234
27． Latham P, Lund EK, Johnson IT. Dietary n-3 PUFA increases the apoptotic response to l,2-dimethylhydrazine,reduces mitosis and suppresses the induction of carcinogenesis in the rat colon.Carcinogenesis, 1999,20(4) :645-50
28． Furukawa F, Nishikawa A, Kitahori Y, Tanakamaru Z, Hirose M. Spontaneous development of aberrant crypt foci in F344 rats.J Exp Clin Cancer Res. 2002;21(2) : 197-201
29． Wali RK, Khare S, Tretiakova M, et al. Ursodeoxycholic acid and F(6) -D(3) inhibit aberrant crypt proliferation in the rat azoxymethane
model of colon cancer: roles of cyclin D1 and E-cadherin.Cancer Epidemiol Biomarkers Prev. 2002;11(12) :1653-1662
30． Bird-RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer[J]. Cancer-Lett, 1995,93(1) : 55-71
31． Rodrigues MA, Silva LA, Salvadori DM, et al. Aberrant crypt foci and colon cancer: comparison between a short-and medium-term bioassay for colon carcinogenesis using dimethylhydrazine in Wistar rats.Braz J Med Biol Res. 2002 ;35(3) :351-355．
32． Takahashi M, Mutoh M, Kawamori T, et al. Altered expression of beta-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis.Carcinogenesis. 2000;21(7) :1319-1327
33． Kishimoto Y, Takata N, Jinnai T, et al. Sulindac and a cyclooxygenase-2 inhibitor, etodolac, increase APC mRNA in the colon of rats treated with azoxymethane. Gut. 2000;47(6) :812-819
34． Katyama M, Yoshimi N, Yamada Y, et al. Preventive effect of fermented brown rice and rice bran against colon carcinogenesis in male F344 rats. Oncol Rep. 2002 ;9(4) :817-822
35． Tanaka T, Kohno H, Shimada R, et al. Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats.Carcinogenesis. 2000;21(6) :1183-1189
36． Papanikolaou A, Wang QS, Delker DA, Rosenberg DW. Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility.Cancer Lett. 1998 ;130(1-2) :29-34
37． Wargovich MJ, Chen CD, Jimenez A, et al.Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat.Cancer Epidemiol Biomarkers Prev 1996;5(5) :355-360
38． Xu M, Bailey AC, Hernaez JF, et al. Protection by green tea, black tea, and indole-3-carbinol against 2-amino-3-methyl limidazo [4,5-f]
quinoline-induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis 1996 ;17(7) :1429-1434
39． Jia XD, Han C. Chemoprevention of tea on colorectal cancer induced by dimethylhydrazine in Wistar rats. World J Gastroenterol 2000 ;6(5) :699-703
40． Rao CV, Simi B, Reddy BS. Inhibition by dietary curcumin of azoxymethane-uiduced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon. Carcinogenesis 1993 Nov;14(11) :2219-2225
41． Ohishi T, Kishimoto Y, Miura N,et al. Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon Carcinogenesis of rats treated with azoxymethane.Cancer Lett. 2002 ;177(1) :49-56
42． Fukushima S, Wanibuchi H, Li W. Inhibition by ginseng of colon Carcinogenesis in rats.J Korean Med Sci. 2001; 16 Suppl:S75-80
43． Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH.Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon Carcinogenesis in mice.Cancer Res. 1994;54(22) :5841-5847
44． Conney AH, Lou YR, Xie JG, et al. Some perspectives on dietary inhibition of Carcinogenesis: studies with curcumin and tea. Proc Soc Exp Biol Med. 1997;216(2) :234-245
45． Kawamori T, Lubet R, Steele VE, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.Cancer Res. 1999;59(3) :597-601
46． Yamane T, Hagiwara N, Tateishi M, et al.Inhibition of azoxymethane-induced colon Carcinogenesis in rat by green tea polyphenol fraction. Jpn J Cancer Res 1991;82(12) :1336-1339
47． Weyant MJ, Carothers AM, Dannenberg AJ, et al. (+)-Catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse.Cancer Res. 2001;61(1) :118-125
48． Hirose M, Hoshiya T, Mizoguchi Y, Nakamura A, Akagi K, Shirai T. Green tea catechins enhance tumor development in the colon without effects in the lung or thyroid after pretreatment with 1,2-Dimethylhydrazine or 2,2'-dihydroxy-di-n-propylnitrosamine in male F344 rats. Cancer Lett 2001;168(1) :23-29
49． Bostick RM, Fosdick L, Lillemoe TJ, et al. Methodological findings and considerations in measuring colorectal epithelial cell proliferation in humans.Cancer Epidemiol Biomarkers Prev. 1997 ;6(11) :931-942
50． Husain SS, Szabo IL, Tamawski AS.NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action. Am J Gastroenterol, 2002;97(3) :542-553
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52． Baron JA, Sandier RS.Nonsteroidal anti nflammatory drugs and cancer prevention.Annu Rev Med. 2000;51:511-523
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54． Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis.J Mol Endocrinol. 2001;27(1) :1-9
55． Maaser K, Daubler P, Barthel B, et al. Oesophageal squamous cell neoplasia in head and neck cancer patients:upregulation of COX-2 during carcinogenesis.Br J Cancer. 2003;88(8) :1217-1222．
56． Ohno S, Tachibana M, Fujii T, et al. Role of stromal collagen in immunornodulation and prognosis of advanced gastric carcinoma.Int J Cancer. 2002;97(6) :770-774
57． Bobbie Z, Muller PY, Heinimann K, et al. Expression of COX-2 and Wnt pathway genes in adenomas of familial adenomatous polyposis patients treated with meloxicam.Anticancer Res. 2002;22(4) :2215-2220
58． Mueller E, Sarraf P, Tontonoz P, et al. Terminal differentiation of human breast cancer through PPAR gamma.Mol Cell. 1998;1(3) :465-470
59． Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma.Nat Med. 1998;4(9) :1046-1052
60． Badawi AF, Badr MZ. Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma and levels of prostaglandin E2 and 15-deoxy-deltal2,14-prostaglandin J2 in human breast cancer and metastasis.Int J Cancer. 2003;103(1) :84-90
61． Wick M, Hurteau G, Dessev C, et al. Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth.Mol Pharmacol. 2002 ;62(5) :1207-1214．
62． Nikitakis NG, Hebert C, Lopes MA, et al. PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells.Int J Cancer. 2002;98(6) :817-823
63． Chauhan DP. Chemotherapeutic potential of curcumin for colorectal cancer.Curr Pharm Des. 2002;8(19) :1695-1706
64． Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000． CA Cancer J Clin. 2000;50(1) :7-33
65． Tattersall MH, Thomas H. Recent advances: oncology. BMJ. 1999 Feb 13;318(7181) :445-448
66． Weisburger JH. Nutritional approach to cancer prevention with emphasis on vitamins,antioxidants, and carotenoids. Am J Clin Nutr. 1991;53(1 Suppl):226S-237S
67． Sharma RA, Manson MM, Gescher A, Steward WP. Colorectal cancer chemoprevention: biochemical targets and clinical development of promising agents. Eur J Cancer. 2001;37(1) :12-22
68． Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001 Jul;7(7) :1894-1900
69． Yoshitani SI, Tanaka T, Kohno H, Takashima S. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. Int J Oncol. 2001;19(5) :929-939
70． Ota S, Bamba H, Kato A, Kawamoto C, Yoshida Y, Fujiwara K. Review article: COX-2, prostanoids and colon cancer. Aliment Pharmacol Ther. 2002;16 Suppl 2:102-106
71． Bakhle YS. COX-2 and cancer: a new approach to an old problem.Br J Pharmacol. 2001; 134(6) : 1137-1150
72． Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994 ;107(4) :1183-1188
73． Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Ape delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2) . Cell. 1996;87(5) :803-809
74． Metz N, Lobstein A, Schneider Y, Gosse F, Schleiffer R, Anton R, Raul F. Suppression of azoxymethane-induced preneoplastic lesions and inhibition of cyclooxygenase-2 activity in the colonic mucosa of rats drinking a crude green tea extract.Nutr Cancer. 2000;38(1) :60-64
75． Goel A, Boland CR, Chauhan DP. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells.Cancer Lett. 2001;172(2) :111-118
76． Mahmoud NN, Boolbol SK, Dannenberg AJ, et al. The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine
model of familial adenomatous polyposis. Carcinogenesis 1998, 19:87-91
77． Piazza GA, Rahm AL, Krutzsch M, et al.: Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995,55:3110-3116
78． Elder DJ, Halton DE, Hague A, et al. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2) -selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 1997, 3:1679-1683
79． Hanif R, Pittas A, Feng Y, et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996, 52:237-245
80． Mansen A, Guardiola-Diaz H, Rafter J, et al.Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa . Biochem Biophys Res Commun. 1996 24;222(3) :844-851
81． Lefebvre AM, Chen I, Desreumaux P, et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 1998, 4:1053-1057
82． Saez E, Tantonoz P, Nelson MC, et al. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 1998, 4:1058-1061
83． Osawa E, Nakajima A, Wada K, et al. Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 2003;124(2) :361-367
84． Kohno H, Yoshitani S, Takashima S, et al. Troglitazone, a ligand for peroxisome proliferator-activated receptor gamma,inhibits chemically-induced aberrant crypt foci in rats.Jpn J Cancer Res. 2001;92(4) :396-403
85． Sarraf P, Mueller E, Smith WM, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell 1999,3:799-804
86． Lehmann JM, Lenhard JM, Oliver BB, et al.Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997, 272:3406-3410
87． Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A 1997, 94:237-241
88． Brockman JA, Gupta RA, Dubois RN. Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology 1998, 115:1049-1055
89． Elstner E, Muller C, Koshizuka K, et al. Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 1998,95:8806-8811
90． Kubota T, Koshizuka K, Williamson EA, et al. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 1998,58:3344-3352
91． Jow L, Mukherjee R. The human peroxisome proliferator-activated receptor (PPAR) subtype NUC1 represses the activation of hPPAR alpha and thyroid hormone receptors. J Biol Chem 1995, 270:3836-3840
92． Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, et al. Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor: possible role of a leucine zipper-like heptad repeat. J Biol Chem 1995, 270:18117-18122
93． Hunter J, Kassam A, Winrow CJ, et al. Crosstalk between the thyroid hormone and peroxisome proliferator-activated receptors in regulating peroxisome proliferator-responsive genes. Mol Cell Endocrinol 1996,116:213-221
94． Miyamoto T, Kaneko A, Kakizawa T, et al. Inhibition of peroxisome proliferator signaling pathways by thyroid hormone receptor: competitive binding to the response element. J Biol Chem 1997, 272:7752-7758
95． Winrow CJ, Kassam A, Miyata KS, et al. Interplay of the peroxisome proliferator-activated receptor and the thyroid hormone receptor-signaling pathways in regulating peroxisome proliferator-responsive genes. Ann N Y Acad Sci 1996, 804:214-230
2． Devasena T, Rajasekaran KN, Menon VP. Bis-1,7-(2-hydroxyphenyl)-hepta-l,6-diene-3,5-dione (a curcumin analog)ameliorates DMH-induced hepatic oxidative stress during colon carcinogenesis. Pharmacol Res. 2002 ;46(1) :39-45
3． Murakami A, Takahashi D, Kinoshita T, et al. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite. Carcinogenesis. 2002;23(5) :795-802
4． Giardiello FM, Yang VW, Hylind LM, et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002;346(14) : 1054-1059
5． Janne PA, Mayer RJ. Chemoprevention of colorectal cancer.N Engl J Med. 2000; 342 (26) : 1960-8
6． Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemoprevention.Ann N Y Acad Sci. 999;889:1-13
7． Badawi AF, Badr MZ. Chemoprevention of breast cancer by targeting cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma. Int J Oncol. 2002;20(6) :1109-1122
8． Spom MB, Suh N.Chemoprevention of cancer.Carcinogenesis. 2000;21(3) :525-30
9． Wargovich MJ. Colon cancer chemoprevention with ginseng and other botanicals.J Korean Med Sci. 2001; 16 Suppl:S81-86
10. Kossoy G, Ben-Hur H, Stark A, et al. Effects of a 15％ orange-pulp diet on tumorigenesis and immune response in rats with colon tumors. Oncol Rep. 2001;8(6):1387-1391
11. Gee JM, Noteborn HP, Polley AC, Johnson IT. Increased induction of aberrant crypt foci by 1,2-dimethylhydrazine in rats fed diets containing purified genistein or genistein-rich soya protein. Carcinogenesis. 2000; 21(12):2255-2259
12. Mahmoud NN, Carothers AM, Grunberger D, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.Carcinogenesis. 2000;21(5):921-927
13. Reddy BS, Hirose Y, Cohen LA, et al. Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention.Cancer Res. 2000; 60(17):4792-4797
14. Dai W, Liu T, Wang Q, et al.Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors.Int J Oncol. 2002;20(1): 121-126
15. Chen H, Zhang ZS, Zhang YL, Zhou DY. Curcumin inhibits cell proliferation by interfering with the cell cycle and inducing apoptosis in colon carcinoma cells. Anticancer Res 1999;19(5A):3675-3680
16．陈宏，张振书，张亚历，等．姜黄素诱导Lovo细胞凋亡．中国中医基础医学杂志 1999．03．28；5(3)：32-34
17．陈宏，张振书，姜泊，等．中药姜黄素抗癌作用及其机制研究．中华流行病学杂志 1998．09．10；19(5-B)：328-329
18．周京旭，张振书，杨希山，等．食用含姜黄素饲料抑制人鼠实验性肝癌。中华预防医学杂志 2002；1．36(5)：360
19. Cerhan JR, Putnam SD, Bianchi GD, et al. Tea consumption and risk of cancer of the colon and rectum. Nutr Cancer. 2001;41(1-2):33-40
20． Naasani I, Oh-Hashi F, Oh-Hara T, et al. Blocking telomerase by dietary polyphenols is a major mechanism for limiting the growth of human cancer cells in vitro and in vivo.Cancer Res. 2003;63(4) :824-830
21． Uesato S, Kitagawa Y, Kamishimoto M, et al. Inhibition of green tea catechins against the growth of cancerous human colon and hepatic epithelial cells.Cancer Lett. 2001;170(1) :41-44
22． Murakami C, Hirakawa Y, Inui H, Nakano Y, Yoshida H. Effect of tea catechins on cellular lipid peroxidation and cytotoxiciry in HepG2 cells.Biosci Biotechnol Biochem. 2002;66(7) : 1559-62
23． Tan X, Zhang Y, Jiang B, et al.Changes in ceramide levels upon catechins-induced apoptosis in LoVo cells. Life Sci 2002;70(17) :2023-2029
24． Tan X, Hu D, Li S, et al. Differences of four catechins in cell cycle arrest and induction of apoptosis in LoVo cells. Cancer Lett 2000; 158(1) : 1-6
25． Borrelli F, Mereto E, Capasso F, et al. Effect of bisacodyl and cascara on growth of aberrant crypt foci and malignant tumors in the rat colon.Life Sci. 2001;69(16) :1871-1877
26． Venkatesan N, Punithavathi D, Arumugam V. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol. 2000; 129(2) :231-234
27． Latham P, Lund EK, Johnson IT. Dietary n-3 PUFA increases the apoptotic response to l,2-dimethylhydrazine,reduces mitosis and suppresses the induction of carcinogenesis in the rat colon.Carcinogenesis, 1999,20(4) :645-50
28． Furukawa F, Nishikawa A, Kitahori Y, Tanakamaru Z, Hirose M. Spontaneous development of aberrant crypt foci in F344 rats.J Exp Clin Cancer Res. 2002;21(2) : 197-201
29． Wali RK, Khare S, Tretiakova M, et al. Ursodeoxycholic acid and F(6) -D(3) inhibit aberrant crypt proliferation in the rat azoxymethane
model of colon cancer: roles of cyclin D1 and E-cadherin.Cancer Epidemiol Biomarkers Prev. 2002;11(12) :1653-1662
30． Bird-RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer[J]. Cancer-Lett, 1995,93(1) : 55-71
31． Rodrigues MA, Silva LA, Salvadori DM, et al. Aberrant crypt foci and colon cancer: comparison between a short-and medium-term bioassay for colon carcinogenesis using dimethylhydrazine in Wistar rats.Braz J Med Biol Res. 2002 ;35(3) :351-355．
32． Takahashi M, Mutoh M, Kawamori T, et al. Altered expression of beta-catenin, inducible nitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesis.Carcinogenesis. 2000;21(7) :1319-1327
33． Kishimoto Y, Takata N, Jinnai T, et al. Sulindac and a cyclooxygenase-2 inhibitor, etodolac, increase APC mRNA in the colon of rats treated with azoxymethane. Gut. 2000;47(6) :812-819
34． Katyama M, Yoshimi N, Yamada Y, et al. Preventive effect of fermented brown rice and rice bran against colon carcinogenesis in male F344 rats. Oncol Rep. 2002 ;9(4) :817-822
35． Tanaka T, Kohno H, Shimada R, et al. Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats.Carcinogenesis. 2000;21(6) :1183-1189
36． Papanikolaou A, Wang QS, Delker DA, Rosenberg DW. Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility.Cancer Lett. 1998 ;130(1-2) :29-34
37． Wargovich MJ, Chen CD, Jimenez A, et al.Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat.Cancer Epidemiol Biomarkers Prev 1996;5(5) :355-360
38． Xu M, Bailey AC, Hernaez JF, et al. Protection by green tea, black tea, and indole-3-carbinol against 2-amino-3-methyl limidazo [4,5-f]
quinoline-induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis 1996 ;17(7) :1429-1434
39． Jia XD, Han C. Chemoprevention of tea on colorectal cancer induced by dimethylhydrazine in Wistar rats. World J Gastroenterol 2000 ;6(5) :699-703
40． Rao CV, Simi B, Reddy BS. Inhibition by dietary curcumin of azoxymethane-uiduced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon. Carcinogenesis 1993 Nov;14(11) :2219-2225
41． Ohishi T, Kishimoto Y, Miura N,et al. Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon Carcinogenesis of rats treated with azoxymethane.Cancer Lett. 2002 ;177(1) :49-56
42． Fukushima S, Wanibuchi H, Li W. Inhibition by ginseng of colon Carcinogenesis in rats.J Korean Med Sci. 2001; 16 Suppl:S75-80
43． Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH.Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon Carcinogenesis in mice.Cancer Res. 1994;54(22) :5841-5847
44． Conney AH, Lou YR, Xie JG, et al. Some perspectives on dietary inhibition of Carcinogenesis: studies with curcumin and tea. Proc Soc Exp Biol Med. 1997;216(2) :234-245
45． Kawamori T, Lubet R, Steele VE, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.Cancer Res. 1999;59(3) :597-601
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