GENE MUTATIONS AND APOPTOSIS IN CANCER CHEMOPREVENTION

克隆性上皮以持续增殖的平衡状态存活 并伴有结肠细胞死亡和/或脱落。最近的证据显示 表明癌基因和抑癌基因起重要作用， 在细胞死亡的独特模式中起作用，称为凋亡。中央 在这个提议中要检验的假设是， 或特定基因表达的改变，影响细胞凋亡， 结肠粘膜细胞增殖。相关的假设是， 基因突变或特定基因表达的改变可能会影响 由饮食因素如胆汁酸诱导的细胞凋亡，以及某些 癌症化学预防剂可能通过诱导 在基因组改变的细胞中选择性凋亡。拟议的研究将 重点关注癌基因Ki-ras和bcl-2的改变以及肿瘤 抑制基因p53和APC以及化学预防剂DFMO， 熊去氧胆酸盐和NSAIDs伊莱克斯和舒林酸砜。 为了检验上述假设，本研究的具体目的是： 建议如下。 “确定特定基因改变对增殖的影响 和细胞凋亡在明显正常和肿瘤结肠组织中获得 从啮齿类动物结肠癌模型。 测量癌症化学预防剂对增殖的影响， 大肠癌细胞凋亡与特异性基因突变 来自动物模型和人类选择的人群的组织。 确定特定的基因突变是否使正常或肿瘤结肠- 衍生的细胞更容易受到癌症化学预防剂诱导 生长抑制或凋亡。 确定特定基因突变是否影响胆汁诱导的细胞凋亡 正常和肿瘤性人结肠源性细胞和结肠 来自啮齿动物和人类的组织。 本提案的长期目标是确定机制， 特异性结肠癌化学预防剂发挥其抗癌作用 为了确定个人的最佳有效应用， 或多种药剂的组合。这项工作的结果应进一步 建立一些结肠癌化学预防剂的基本原理， 可以定义新的和更有效的策略来治疗或预防结肠炎 癌

Clonic epithelium survives in a balanced state of continuous proliferation coupled with colonocyte death and/or shedding. Recent evidence now demonstrates that oncogenes and tumor suppressor genes play important roles in a unique mode of cell death, termed apoptosis. The central hypothesis to be tested in this proposal is that specific gene mutations, or alterations in specific gene expression, affect apoptosis as well as cell proliferation in colonic mucosa. Related hypotheses are that specific gene mutations or alterations in specific gene expression may affect apoptosis induced by dietary factors, such as bile acids, and certain cancer chemopreventive agents may work via mechanisms that induce apoptosis selectively in genomically altered cells. Proposed studies will focus on alterations in the oncogenes Ki-ras and bcl-2 and the tumor suppressor genes p53 and APC and the chemopreventive agents DFMO, ursodeoxycholate and the NSAIDs Ibuprofen and sulinidac sulfone. In order to test the hypotheses stated above, the Specific Aims of this proposal are as follows. "Determine the consequences of specific gene alterations on proliferation and apoptosis in apparently normal and neoplastic colonic tissues obtained from rodent models of colon carcinogenesis. Measure the effects of cancer chemopreventive agents on proliferation, apoptosis and specific gene mutations in normal and neoplastic colorectal tissue from animal models and human selected human populations. Determine if specific gene mutations render normal or neoplastic colon- derived cells more susceptible to cancer chemopreventive agent-induced growth inhibition or apoptosis. Determine if specific gene mutations influence apoptosis induced by bile acids in normal and neoplastic human colon-derived cells and colonic tissues derived from rodents and humans. The long term goal of this proposal is to define the mechanisms by which specific colon cancer chemopreventive agents exert their anti-carcinogenic effects in order to define optimally effective applications of individual, or combinations of multiple, agents. Results from this work should further establish the rationale for some colon cancer chemopreventive agents, and may define new and more effective strategies to treat or prevent colon cancer.