STUDIES OF CARCINOGENICITY OF FECAPENTAENES

人类粪便中含有一组高度致突变的化合物 叫做非卡喷他烯。 这些化合物产生多种遗传毒性 方面的影响. 它们是直接作用的诱变剂，增加大鼠的DNA合成 在小鼠BALB/c3 T3细胞中诱导肿瘤转化， 导致DNA单链断裂，姐妹染色单体交换和突变， 人成纤维细胞。 上述研究结果表明， 人类大肠癌的病因可能已经被发现。 然而，到目前为止，成功证明了非卡喷他烯诱导的 体内致癌作用尚未完成。 重大问题的 可以解释这些负面的结果已经有缺陷的处理 非常不稳定的化合物非卡五烯;不适当的溶剂; 动物模型不足。 目前的主要目标 建议是确定fecapentaenes是否可以产生全部或部分 实验性大肠粘膜的肿瘤反应 动物 用于防止非卡喷他烯分解的方法将 被雇用。 短期体内试验系统将用于确定 溶剂、给药条件和给药方案最有可能导致 致癌反应 这些措施包括评估 大肠隐窝的增殖区室，测定 有丝分裂活动增加的存在， 核畸变和异常隐窝形成的研究。 采用上述确定的最佳条件， 将进行研究以确定fecapentaene：（1）是否是完全的 致癌物，（2）是肿瘤引发剂，（3）是肿瘤促进剂，（4）可以 导致肿瘤进展，和/或（5）在肿瘤中具有共致癌特性， 大肠粘膜。 如果获得积极的结果，他们可能 形成评价非卡喷他烯致癌危害的基础， 的预防手段。

Human feces has been found to contain a group of highly mutagenic compounds called fecapentaenes. These compounds produce a variety of genotoxic effects. They are direct acting mutagens, increase DNA synthesis in rat hepatocytes, induce neoplastic transformation in mouse BALB/c3T3 cells and cause DNA single strand breaks, sister chromatid exchanges and mutations in human fibroblasts. The above findings suggest that a major factor in the causation of cancer of the large bowel in the human may have been found. However, thus far, a successful demonstration of fecapentaene-induced carcinogenesis in vivo has not been accomplished. Major problems that could account for these negative results have been defective handling of the fecapentaenes which are very labile compounds; inappropriate solvents; and inadequate animal models. The primary objective of the present proposal is to determine if fecapentaenes can produce a full or partial neoplastic response in the mucosa of the large bowel in experimental animals. Methodology for preventing decomposition of the fecapentaene will be employed. Short-term in vivo test systems will be used to determine the solvent, delivery conditions and dose schedule most likely to result in a carcinogenic response. These include assessment of expansion of the proliferative compartment of the crypts of the large bowel, determination of the presence of increased mitotic activity, studies of formation of nuclear aberrations, and studies of formation of aberrant crypts. Employing optimal conditions ascertained from the above, carcinogenesis studies will be undertaken to determine if fecapentaene: (1) is a full carcinogen, (2) is a tumor initiator, (3) is a tumor promoter, (4) can cause tumor progression, and/or (5) has syncarcinogenic properties in the mucosa of the large bowel. If positive results are obtained, they could form a basis evaluating the carcinogenic hazard from fecapentaenes and means of its prevention.