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Study on the development of the short-term screening model for chemical carcinogenic agents and its application in relation to biliary tract cancer.

化学致癌剂短期筛查模型的建立及其在胆道癌中的应用研究。

基本信息

批准号：
62570610
负责人：
MIYAZAKI Kohji
金额：
$ 1.34万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

To develop a useful test for the short-term screening of carcinogenic agents in relation to biliary tract cancer we measured unscheduled DUA synthesis (UDS) in bovine bile duct epithelial cells in culture induced by MNNG, ENNG, MCA, DMN and AFB_1 which were used successfully in developing biliary tract neoplasms in experimental animals. MNNG and ENNG induced UDS without addition of S9. MCA elicited UDS only if S9 was added. Regardless of the presence or abscence of S9, DMN failed to induce UDS. DNA repair by AFB_1 was enhanced by the presence of S9. On the contrary in human gallbladder epithelial cells MCS and DMN induced UDS even in the abscence of S9 indicating the presence of activating system of MCS and DMN in human gallbladder epithelium. By applying more sensitive alkaline and neutral elution technique we successfully demonstrated DNA single-strand breaks by these agents in bovine bile duct epithelial cells. Thus alkaline and neutral elution/ primary biliary tract epithelial cell culture system provides an organ specific model than UDS for detecting genotoxicities of chemical agents to the biliary tract. Phospholipase A_2 and lysolecithin which are supposed to play a significant role in the carcinogenesis of the biliary tract in anomalous pancreatico-biliary duct union did not induce significant DNA strand breaks, which suggests neither of them is an initiator of the carcinogenesis by itself.

为了建立一种短期筛选与胆道癌相关的致癌物质的有效方法，我们测定了MNNG、ENNG、MCA、DMN和AFB_1诱导的培养牛胆管上皮细胞的非计划DUA合成（UDS），这些细胞已成功地用于实验动物胆道肿瘤的形成。在不添加S9的情况下，MNNG和ENNG诱导UDS。MCA仅在添加S9时才会触发UDS。无论S9是否存在，DMN都不能诱导UDS。S9的存在增强了AFB_1对DNA的修复作用。而在人胆囊上皮细胞中，MCS和DMN在没有S9的情况下也能诱导UDS，说明人胆囊上皮中存在MCS和DMN激活系统。通过使用更灵敏的碱性和中性洗脱技术，我们成功地证明了这些药物在牛胆管上皮细胞中的DNA单链断裂。因此，碱性和中性洗脱/原代胆道上皮细胞培养系统为检测化学制剂对胆道的遗传毒性提供了一种器官特异性模型。磷脂酶A_2和溶卵磷脂在胰胆管异常结合的胆道癌变中起重要作用，但DNA链断裂不明显，提示它们本身都不是癌变的引发剂。