PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

乳清酸促进肝癌发生

• 批准号: 3174745
• 负责人: DITTAKAVI S SARMA
• 金额: $ 9.07万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3174745
• 关键词: chemical carcinogen; chemical carcinogenesis; high performance liquid chromatography; histochemistry /cytochemistry; histopathology; lipid metabolism; nucleic acid chemical synthesis; orotate; paper chromatography; peroxidation; radiotracer; thin layer chromatography; tumor promoters; ultraviolet spectrometry

The present proposal stems from our recent observations that orotic acid, a precursor of pyrimidine nucleotides is not only an excellent liver tumor promoter but also has the potential to be a multiorgan tumor promoter. Unlike most of the tumor promoters, orotic acid does not induce cell proliferation either in the liver or in the colon, the 2 organs examined. A new hypothesis was postulated i.e. an imbalance in nucleotide pools such as the one that occurs following orotic acid feeding appears to play an important role in the promotion phase of the carcinogenic process. In the present proposal experiments are designed to characterize the Orotic Acid Model of liver tumor promotion in greater detail. In order to study the mechanism of tumor promotion, in the present proposal experiments are designed to obtain far fewer nodules but with increased probability of progressing to cancer. For example rats will be initiated with diethylnitrosamine and will be exposed to 1% orotic acid 5 or 10 weeks after initiation rather than 1 week after initiation. In a preliminary experiments such a protocol resulted in 1 or 2 nodules per rat with 100% incidence of nodules at the end of 20-40 weeks, and with 1 hepatocellular carcinoma. To test the multiorgan tumor potential of orotic acid, the effect of orotic acid on the intestinal carcinogenesis initiated with azoxymethane and on the urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl) nitrosamine will be tested. Preliminary results indicated that orotic acid does indeed promote intestinal carcinogenesis initiated with azoxymethane. Some attractive features of this model that have human relevance are, orotic acid is a normal cellular constituent and present in the cow's milk in considerable quantities. Increased orotic acid in milk, serum and urine occurs in some hereditary disorders and such and increase can also be achieved by metabolic disturbances and dietary means such as high protein or amino acids intake. Unfortunately, disturbances of this kind and high protein intake are not uncommon in human population at large.

目前的提议源于我们最近的观察，即 玫瑰酸，一种嘧啶核苷酸的前体，不仅是一种 优秀的肝脏肿瘤促进剂，但也有可能成为 多器官肿瘤促进剂。与大多数肿瘤促进剂不同， 乳清酸不能诱导肝脏或肝脏中的细胞增殖 在结肠中，检查两个器官。一个新的假设是 假设的，即核苷酸池中的不平衡，例如 在喂食口腔酸后发生的这种情况似乎对 在致癌物质的促进期发挥重要作用 进程。 在本方案中，设计实验是为了表征 更详细的促进肝脏肿瘤的乳清酸模型。 为了研究肿瘤促进作用的机制，在 目前的提议实验旨在获得更少的 结节，但进展为癌症的可能性增加。 例如，大鼠将被二乙基亚硝胺启动，并将 在入门后5周或10周内暴露于1%的奥罗里酸中 印心后不到1周。在初步实验中， 方案导致每只大鼠有1到2个结节，发病率为100% 20-40周末有结节，有1个肝细胞 癌症。 为了测试冬凌草酸的多器官肿瘤潜能， 口香酸对小鼠肠道致癌作用的研究 偶氮甲烷及其对膀胱癌发生的影响 用N-丁基-N-(4-羟基丁基)亚硝胺进行检测。 初步结果表明，奥罗里酸确实能促进 肠道癌变是由偶氮甲烷引发的。 这个模型的一些与人类相关的吸引人的特征 是一种正常的细胞成分，存在于 有相当数量的牛乳。口服液中乳酸量增加 牛奶、血清和尿液存在于一些遗传性疾病和 这种和增加也可以通过代谢紊乱来实现 以及饮食方式，如高蛋白质或氨基酸的摄入。 不幸的是，这种干扰和高蛋白摄入量 在人类群体中并不少见。