PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

目前的建议源于我们最近的观察， 乳清酸，嘧啶核苷酸的前体，不仅是 优秀的肝肿瘤促进剂，但也有可能成为一个 多器官肿瘤促进剂 与大多数肿瘤促进剂不同， 乳清酸不诱导肝或肝内的细胞增殖， 在结肠中，检查了两个器官。 一个新的假设是， 假设，即核苷酸库中的不平衡，例如 乳清酸喂养后发生的变化似乎起着 在致癌物质的促进阶段起重要作用 过程 在本提案中，实验旨在表征 乳清酸模型的肝肿瘤促进更详细。 为了研究促癌机制，在 目前的建议实验旨在获得少得多 结节，但进展为癌症的可能性增加。 例如，大鼠将开始与二乙基亚硝胺， 在开始后5或10周暴露于1%乳清酸，而不是 开始后1周。 在这样的初步实验中， 方案导致每只大鼠1或2个结节， 20-40周结束时出现结节，1个肝细胞 carcinoma. 为了测试乳清酸的多器官肿瘤潜力， 乳清酸对肠道癌变的影响 氧化偶氮甲烷对膀胱癌发生的影响 将测试N-丁基-N-（4-羟丁基）亚硝胺。 初步结果表明，乳清酸确实能促进 由氧化偶氮甲烷引发的肠道致癌作用。 这个模型的一些吸引人的特征与人类相关 乳清酸是一种正常的细胞成分，存在于 大量的牛奶。 乳清酸增加， 牛奶、血清和尿液会出现在某些遗传性疾病中， 这种增加也可以通过代谢紊乱来实现 和饮食手段，如高蛋白质或氨基酸摄入。 不幸的是，这种干扰和高蛋白质摄入 在人类中并不罕见

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.