RETINOIDS INHIBIT CYCLOOXYGENASE AND CARCINOGENESIS

这项建议的总体目标是增进我们对 环氧合酶(COX)催化的反应在发病机制中的重要性 乳腺癌的风险。考克斯可能很重要，因为i)它将 对具有致突变性的活性亲电体的化学物质，以及ii)它 催化前列腺素(PGs)的产生。PGS被认为是 在肿瘤发生的后启动阶段很重要。特例 人们的注意力将集中在COX-2上，这是一种最近发现的酶，它可以 可由细胞因子、生长因子和肿瘤促进剂诱导。我们有 研究表明，维甲酸包括N-(4-羟基苯基)维甲酰胺(4-HPR) 下调乳腺上皮细胞环氧合酶-2基因的表达 抑制PGs的合成。抑制的理论益处 COX已被研究证实，抑制COX的药物， 例如阿司匹林，预防癌症。我们的结果建立了一个重要的 两大类化学预防药物之间的机械联系： PG合成和维甲酸的抑制剂。此外，我们的结果是 对解释为什么类维A酸类药物对 预防乳腺癌。这项提案的目标是 1)定义维甲酸下调血管紧张素转换酶的机制 COX-2基因在乳腺上皮细胞中的表达我们会 确定AP-1转录因子和雌激素的重要性 受体在调节这一效应中的地位。2)提高对……的认识 环氧合酶催化反应在癌症发病机制中的重要性。 我们将确定COX-2水平的增加是否会影响 外源物质对近致癌物或细胞的代谢 扩散。3)确定COX-2的表达增加是否 至少对#年PGE/2生产过剩负有部分责任 恶性乳腺组织。确定增产的基础 恶性组织中PGs的表达可能是开发新的 治疗方法。必须强调的是， 这些实验可能会得到广泛的应用。我们知道，对于 例如，PG合成的抑制剂可以预防结肠癌。 此外，维甲酸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.