Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.
Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.
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DOI：
10.1093/carcin/21.6.1149
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发表时间：
2000-06
期刊：
影响因子：
4.7
通讯作者：
M. Wargovich;Arnaldo Jimenez;Kathy McKee;V. Steele;M. Velasco;Johnnie Woods;R. Price;K. Gray
中科院分区：
文献类型：
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作者：
M. Wargovich;Arnaldo Jimenez;Kathy McKee;V. Steele;M. Velasco;Johnnie Woods;R. Price;K. Gray
我们使用两种测定法评估了 78 种潜在化学预防剂对 F344 大鼠的作用，其中对结肠中致癌物诱导的异常隐窝病灶 (ACF) 的抑制是疗效的衡量标准。在这两项试验中，F344 大鼠每周连续注射两次剂量为 15 mg/kg 的致癌物氧化偶氮甲烷 (AOM)，可诱导 ACF。最后一次 AOM 注射两周后，评估动物在亚甲蓝染色的整个大鼠结肠中检测到的异常隐窝的数量。在启动阶段，在 AOM 给药期间给予方案药物，而在启动后测定中，在 8 周测定的最后 4 周（此时 ACF 已进展到多个隐窝簇）引入化学预防剂。这些药物是根据文献中的化学预防活性报告和/或体外致癌模型的功效数据而得出的优先列表。在起始阶段，羧基酰胺咪唑、对氯苯乙酸酯、马来酸扑尔敏、D609、双氯芬酸、依托哌酮、二十碳四烯酸、金合欢醇、阿魏酸、番茄红素、氯苯甲嗪、蛋氨酸、异硫氰酸苯己酯、丁酸苯酯、吡罗昔康、9-顺式视黄酸、S-烯丙基半胱氨酸、牛磺酸、四环素和维拉帕米是ACF的强抑制剂。在启动后阶段，阿司匹林、葡萄糖二酸钙、酮洛芬、吡罗昔康、9-顺式视黄酸、视黄醇和芦丁抑制ACF向多个隐窝簇的生长。基于这些数据，某些植物化学物质、抗组胺药、非甾体抗炎药和类维生素A显示出对结肠癌化学预防的独特临床前前景，后两类药物在癌发生后起始阶段特别有效。
We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.