GENE MUTATIONS AND APOPTOSIS IN CANCER CHEMOPREVENTION

克隆上皮在持续增殖的平衡状态下存活 伴随着结肠细胞死亡和/或脱落。最近的证据现在 表明癌基因和肿瘤抑制基因发挥着重要作用 在一种独特的细胞死亡模式中发挥作用，称为细胞凋亡。中环 在这项提议中要检验的假设是特定的基因突变， 或特定基因表达的改变，会影响细胞凋亡 结肠粘膜细胞增殖。相关的假设是具体的 基因突变或特定基因表达的变化可能会影响 由饮食因素诱导的细胞凋亡，如胆汁酸和某些 癌症化学预防药物可能通过诱导 选择性地在基因改变的细胞中进行细胞凋亡。拟议的研究将 关注癌基因Ki-ras和bcl-2的变化与肿瘤 抑癌基因P53和APC以及化学预防药物DFMO， 熊去氧胆酸盐和非甾体抗炎药布洛芬和舒林德砜。 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 和明显正常和肿瘤结肠组织中的细胞凋亡 来自结肠癌的啮齿动物模型。 测量癌症化学预防药物对细胞增殖的影响， 正常和肿瘤大肠组织中细胞凋亡和特异性基因突变的研究 取自动物模型和人类选定的人类种群的组织。 确定特定的基因突变是否会导致正常或肿瘤结肠- 衍生细胞对化学防癌剂诱导的癌症更敏感 生长抑制或细胞凋亡。 确定特定基因突变是否影响胆汁诱导的细胞凋亡 正常人和肿瘤人结肠来源细胞和结肠中的酸 来自啮齿动物和人类的组织。 这项提案的长期目标是确定 特定的结肠癌化学预防药物发挥抗癌作用 效果为了定义个人的最佳有效应用， 或多个代理的组合。这项工作的结果应该进一步 建立一些结肠癌化学预防药物的理论基础，以及 可能会定义新的更有效的治疗或预防结肠癌的策略 癌症。

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.