LIVER TUMOR PROMOTION IN SPARSE FUR MUTANT MICE

本提案的长期目标是确定是否 与水平升高相关的代谢和遗传障碍 奥罗里酸的风险更高。其基本原理是 这源于我们的观察：(I)玫瑰花酸，一种正常的细胞 成分是一种多器官肿瘤促进剂，(Ii)是 嘧啶核苷酸，接触奥罗里酸会导致水平升高 尿苷核苷酸和这种核苷酸不平衡的产生 PEOLS是冬凌草酸发挥促癌作用所必需的；以及 (Iii)饲喂缺乏精氨酸的饮食，精氨酸是一种尿素循环氨基酸引起的 尿素循环中的扰动，这种扰动不仅导致 口香酸和肝组织尿苷核苷酸水平升高，但也 对大鼠和小鼠肝脏均有促瘤作用。稀疏 毛皮突变(SPF/Y)小鼠90%缺乏鸟氨酸转氨酶 (OTC)一种尿素循环酶。这种缺陷与高水平有关。 和肝脏核酸库的不平衡。我们建议 用这些突变的小鼠作为一个模型系统来研究这个问题 与更高水平的口交相关的代谢和遗传疾病 酸性和尿苷核苷酸会增加肿瘤促进的风险。在……里面 这项拟议的研究，无论是突变的雄鼠还是正常的雄鼠， 瑞士ICR雄性小鼠将暴露于肝脏致癌物质的剂量 它们本身不会在正常小鼠中诱发肝细胞癌，除非 升职了。据预测，引发稀毛突变的小鼠 有较高水平的玫瑰花酸会患上肝细胞癌 即使在没有任何外源性肿瘤促进剂的情况下， 正常对照除非暴露于外源启动子，否则不会发育。在……里面 在下一个系列中，我们将确定这样的癌症发病率是否会 给予膦酰乙酰-L-天冬氨酸和腺嘌呤后降低 它们抑制了口香酸的合成及其向尿苷的转化 分别为核苷酸。这项实验应该表明， SPF/y小鼠对致癌物诱导的肿瘤易感性增加 是因为高水平的玫瑰酸和相关的不平衡 核苷酸池或由于与 突变的小鼠。

The long term goal of the present proposal is to determine whether metabolic and genetic disorders that are associated with increased levels of orotic acid are at a higher risk of tumor promotion. The rationale for this stems from our observations: (i) orotic acid, a normal cellular constituent is a multi-organ tumor promoter, (ii) being a precursor of pyrimidine nucleotides, exposure to orotic acid results in increased levels of uridine nucleotides and creation of such an imbalance in nucleotide pools is essential for orotic acid to exert its tumor promoting effect; and (iii) feeding a diet deficient in arginine, a urea cycle amino acid induces disturbances in urea cycle, and such perturbations not only result in increased levels of orotic acid and hepatic uridine nucleotides but also exert tumor promoting effect in the livers of both rats and mice. Sparse fur mutant (spf/y) mice are 90% deficient in ornithine transcarbamylase (OTC) a urea cycle enzyme. This deficiency is associated with high levels of orotic acid and an imbalance in hepatic nucleotide pools. We propose to use these mutant mice as a model system to examine the question whether metabolic and genetic disorders associated with higher levels of orotic acid and uridine nucleotides post increased risk of tumor promotion. In the proposed study, both mutant male mice and the normal counterparts, Swiss ICR male mice will be exposed to liver carcinogens at doses which by themselves do not induce liver cell cancer in the normal mice unless promoted. It is anticipated that initiated sparse fur mutant mice which have higher levels of orotic acid will develop hepatocellular carcinoma even in the absence of any exogenous tumor promoter, while the initiated normal controls will not develop unless exposed to exogenous promoter. In the next series we will determine whether such cancer incidence can be decreased by administering phosphonylacetyl-L-aspartic acid and adenine which inhibit the synthesis of orotic acid and its conversion to uridine nucleotides respectively. This experiment should indicate whether the increased susceptibility of spf/y mice to carcinogen-induced tumorigenesis is because of high levels of orotic acid and the associated imbalance in nucleotide pools or due to some other abnormality associated with the mutant mice.