LIVER TUMOR PROMOTION IN SPARSE FUR MUTANT MICE

本提案的长期目标是确定 代谢和遗传疾病，与增加的水平 乳清酸的浓度越高，肿瘤发生的风险越高。 的理由 这源于我们的观察：（i）乳清酸，一种正常的细胞 该成分是多器官肿瘤促进剂，（ii）是 嘧啶核苷酸，暴露于乳清酸导致水平增加 尿苷核苷酸的不平衡和核苷酸不平衡的产生 库是乳清酸发挥其促肿瘤作用所必需的; (iii)喂养缺乏精氨酸的饮食，尿素循环氨基酸诱导 尿素循环中的扰动，并且这种扰动不仅导致 乳清酸和肝尿苷核苷酸水平升高， 在大鼠和小鼠的肝脏中均具有促肿瘤作用。 稀疏 Fur突变（SPF/Y）小鼠90%缺乏鸟氨酸转氨甲酰酶 (OTC)尿素循环酶。 这种缺陷与高水平 乳清酸和肝脏核苷酸库失衡。 我们建议 用这些突变小鼠作为模型系统来研究是否 与高水平乳清酸相关的代谢和遗传疾病 酸和尿苷核苷酸后增加的肿瘤促进的风险。 在 这项拟议中的研究，无论是突变雄性小鼠还是正常小鼠， 瑞士ICR雄性小鼠将暴露于肝脏致癌物的剂量， 它们本身不会在正常小鼠中诱发肝细胞癌，除非 推进 预计启动的稀疏皮毛突变小鼠， 乳清酸水平较高会发展成肝细胞癌 即使在没有任何外源性肿瘤促进剂的情况下， 正常对照将不发育，除非暴露于外源启动子。 在 下一个系列，我们将确定这种癌症的发病率是否可以 给予膦酰乙酰-L-天冬氨酸和腺嘌呤降低 其抑制乳清酸的合成及其向尿苷的转化 核苷酸分别。 这个实验应该表明， spf/y小鼠对致癌物诱导的肿瘤发生的易感性增加 是因为高水平的乳清酸和相关的不平衡， 核苷酸池或由于与细胞凋亡相关的一些其他异常， 突变小鼠

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.