RETINOIDS INHIBIT CYCLOOXYGENASE AND CARCINOGENESIS

本建议的总体目标是加强我们对 环氧合酶（考克斯）催化反应在发病机制中的重要性 乳腺癌 考克斯是潜在的重要，因为i）它转换 化学物质转化为致突变的反应性亲电体，以及ii）它 它催化前列腺素（PGs）的产生。 PG被认为是 在肿瘤发生的后起始阶段很重要。 特别 注意力将集中在考克斯-2上，这是一种最近鉴定的酶， 可由细胞因子、生长因子和肿瘤促进剂诱导。 我们有 显示包括N-（4-羟苯基）维A酰胺（4-HPR）在内的类维生素A 下调乳腺上皮细胞中考克斯-2基因的表达 并抑制前列腺素的合成。 抑制的理论好处 考克斯已经被研究证实，研究表明抑制考克斯的药物， 例如阿司匹林，预防癌症。 我们的研究结果建立了一个重要的 两大类化学预防剂之间的机械联系： PG合成抑制剂和类维生素A。 此外，我们的结果是 在解释类维生素A有效的原因方面可能很重要， 预防乳腺癌。 本提案的目标是 以下内容：1）定义维甲酸下调 考克斯-2基因在乳腺上皮细胞中的表达。 我们将 确定AP-1转录因子和雌激素 受体状态介导这种作用。 2)提高认识 Cox催化反应在癌症发病机制中的重要性。 我们将确定增加的考克斯-2水平是否影响 外源性物质代谢为近似致癌物或细胞 增殖 3)确定考克斯-2表达的增加是否是 至少部分负责PGE/2的过度生产， 恶性乳腺组织 确定增产的基础 恶性组织中PG的含量可能是开发新的 治疗方法。 必须强调的是， 这些实验可能具有广泛的适用性。 我们知道，因为 例如，PG合成的抑制剂可以预防结肠癌。 此外，类维生素A正在多种人类化学预防中进行测试 审判

The overall goal of this proposal is to enhance our understanding of the importance of cyclooxygenase (Cox)-catalyzed reactions in the pathogenesis of breast cancer. Cox is potentially important because i) it converts chemicals to reactive electrophiles that are mutagenic and ii) it catalyzes the production of prostaglandins (PGs). PGs are believed to be important in the post-initiation phases of tumorigenesis. Particular attention will be directed toward Cox-2, a recently identified enzyme that can be induced by cytokines, growth factors and tumor promoters. We have shown that retinoids including N-(4-hydroxyphenyl) retinamide (4-HPR) downregulate the expression of the Cox-2 gene in mammary epithelial cells and inhibit the synthesis of PGs. The theoretical benefits of inhibiting Cox have been confirmed by studies showing that drugs that inhibit Cox, e.g. aspirin, protect against cancer. Our results establish an important mechanistic link between two major classes of chemopreventive agents: inhibitors of PG synthesis and retinoids. Moreover, our results are potentially important in explaining why retinoids are effective in preventing mammary cancer. The objectives of this proposal are the following: 1) Define the mechanism by which retinoids downregulate the expression of the Cox-2 gene in mammary epithelial cells. We will determine the importance of AP-1 transcription factors and estrogen receptor status in mediating this effect. 2) Enhance our understanding of the importance of Cox-catalyzed reactions in the pathogenesis of cancer. We will determine if increased levels of Cox-2 affect either the metabolism of xenobiotics to proximate carcinogens or cellular proliferation. 3) Determine whether increased expression of Cox-2 is responsible at least, in part, for the overproduction of PGE/2 in malignant breast tissue. Defining the basis for the increased production of PGs in malignant tissue could be an important step in developing new therapeutic approaches. It is important to stress that the results of these experiments are likely to be broadly applicable. We know, for example, that inhibitors of PG synthesis protect against colon cancer. Moreover, retinoids are being tested in multiple human chemoprevention trials.