BIOCHEMICAL EFFECTORS OF GENE MUTATED IN COLON CANCER

申请人简介：这项研究的长期目标是 制定合理无毒的结肠癌化学预防策略， 基于结肠癌发生机制的研究。核心假设是 在这项提案中测试的是影响多胺、前列腺素的蛋白质 和/或一氧化氮代谢是结肠癌风险的生化效应因子 与APC和P53抑癌基因突变以及 Ki-ras癌基因。多胺、前列腺素和/或硝酸盐水平的变化 然后，氧化物通过调节结肠癌的表达促进结肠癌的发生 其他基因和代谢过程，进而指导特定的肿瘤 细胞行为，包括细胞凋亡。这一假设的推论是 结肠癌预防的启动后战略将需要不止 一次干预。另一个推论是肠腔因子，如 因为来自肠道细菌和/或饮食来源的多胺可能是 危险因素，饮食精氨酸可能是结肠癌的拮抗剂 人类。该提案的具体目标是确定机制 对参与的特定基因的表达变化负责 多胺、前列腺素和一氧化氮代谢 APC、P53抑癌基因和Ki-ras癌基因突变； 比较多胺抑制剂、前列腺素和硝酸甘油的作用 单独和联合作用于肠道和结肠的氧化物代谢 结肠癌发生的基因改变啮齿动物模型中的癌变； 为了衡量膳食补充剂的效果，包括多胺和 精氨酸，单独或与多胺、前列腺素抑制剂联合使用 和一氧化氮代谢在基因改变的结肠癌发生中的作用 啮齿动物模型；为了确定特定突变的后果， 化学预防药物和/或膳食补充剂对基因表达的影响 与多胺、前列腺素的代谢和含量有关， 结肠粘膜组织中神经酰胺和精氨酸的含量及其相关变化 特定细胞行为的参数，包括细胞凋亡。这些研究是 与当前和未来的一些临床癌症化学预防有关 试验，包括那些使用非类固醇抗炎药的试验 (非甾体抗炎药)和多胺合成的抑制剂。

APPLICANT'S DESCRIPTION: The long-term objective of this research is to develop rational and non-toxic strategies for colon cancer chemoprevention, based on mechanisms of colon carcinogenesis. The central hypothesis to be tested in this proposal is that proteins affecting polyamine, prostaglandin and/or nitric oxide metabolism are biochemical effectors of colon cancer risk associated with mutations in the APC and p53 tumor suppressor genes and the Ki-ras oncogene. Altered levels of polyamines, prostaglandins and/or nitric oxide then facilitate colonic carcinogenesis by modulating the expression of other genes and metabolic processes, which in turn direct specific neoplastic cell behaviors, including apoptosis. A corollary of this hypothesis is that post-initiation strategies for colon cancer prevention will require more than one intervention. Another corollary is that intestinal luminal factors, such as polyamines derived from enteric bacteria and/or dietary sources, may be risk factors, and dietary arginine may be an antagonist, of colon cancer in humans. The Specific Aims of the proposal are to determine the mechanisms responsible for the altered expression of specific genes involved in polyamine, prostaglandin and nitric oxide metabolism, as a consequence of mutations in the APC and p53 tumor suppressor genes and the Ki-ras oncogene; to compare the effects of inhibitors of polyamine, prostaglandin and nitric oxide metabolism alone and in combination on intestinal and colonic carcinogenesis in genetically altered rodent models of colon carcinogenesis; to measure the effects of dietary supplements, including polyamines and arginine, alone or in combination with inhibitors of polyamine, prostaglandin and nitric oxide metabolism on colon carcinogenesis in genetically altered rodent models; and to determine the consequences of specific mutations, chemopreventive drugs and/or dietary supplements on the expression of genes involved in the metabolism of, and contents of, polyamines, prostaglandins, ceramide and arginine in colonic mucosal tissues and relate changes in these parameters to specific cell behaviors, including apoptosis. These studies are relevant to a number of current and future clinical cancer chemoprevention trials, including those employing non-steroidal anti-inflammatory drugs (NSAIDs) and inhibitors of polyamine synthesis.