CANCER CAUSE AND PREVENTION RESEARCH

该研究计划的总体目标是提供新的 这些信息将增加我们对癌症病因的理解， 为预防癌症提供了新的方法。 拟议 研究涉及： (1)最终致突变和致癌代谢产物的鉴定 多环芳烃和相关的含氮化合物 杂环碳氢化合物 其中一个重要目的是 研究是为了加强我们对探索不足的方面的理解， 环境中二醇环氧化物构效关系 重要的多环芳烃及其相关的氮- 含有杂环。 (2)致癌和致突变的光学活性 多环芳烃的R，S，S，R湾区二醇环氧化物和 含氮类似物。 在本研究中，我们将使用R，S，S，R 海湾地区二醇环氧化物（最终诱变剂和致癌物）及其 近缘光学活性但生物活性较低或无活性 几种多环和氮杂多环芳烃的S，R，R，S对映体 碳氢化合物作为探针，用于识别重要的细胞靶点， 致突变和致癌作用。 我们将确定 DNA碱基序列上的光学活性湾区二醇环氧化物对映体 在内源性次黄嘌呤的编码区 中国仓鼠V-79细胞的磷酸核糖基转移酶（HPRT）基因。 我们 还将评估我们的机制和可能的体内意义， 最近观察到的剂量依赖性差异， V-79细胞中R，S，S，R湾区二醇环氧化物的突变。 我们将确定发生在p53和p54基因中的突变类型是否与基因突变有关。 接受高剂量二醇的动物肿瘤中的ras基因 与肿瘤中发生的突变相同或不同 从接受低剂量致癌物的动物身上。 一个重要目标 我们研究的一个目的是比较光学纯的 R，S，S，R湾区二醇环氧化物在V-79细胞中的体外突变 这些化合物在体内的分布。 (3)天然存在的膳食成分的抑制作用， 其衍生物对化学致癌作用和紫外线诱导的 致癌作用 在这项研究中，我们将尝试识别潜在的 有用的致癌抑制剂，并将这些抑制剂用作工具， 以更好地了解致癌过程。 我们将评估（a） 姜黄素、鼠尾草酚、熊果酸、迷迭香 茶和其他膳食植物物质对化学致癌作用的影响， 紫外线诱导的致癌作用，（B）潜在的抑制和/或 1 α，25-二羟维生素D_3对化学物质刺激作用 致癌作用和紫外线诱发的致癌作用，以及（c）影响 化学预防物质对皮肤生长和进展的影响 乳头状瘤 将对可能的作用机制进行评价。

The overall objective of the proposed research program is to provide new information that will increase our understanding of cancer causation and provides new approaches for the prevention of cancer. The proposed research is concerned with: (1) identification of ultimate mutagenic and carcinogenic metabolites of polycyclic aromatic hydrocarbons and related nitrogen-containing heterocyclic hydrocarbons in our environment. An important aim of this research is to enhance our understanding of poorly explored aspects of structure-activity relationships of diol epoxides from environmentally important polycyclic aromatic hydrocarbons and their related nitrogen- containing heterocycles. (2) mechanisms of carcinogenesis and mutagenesis by optically active R,S,S,R bay-region diol epoxides of polycyclic aromatic hydrocarbons and their nitrogen-containing analogs. In this research, we will use R,S,S,R bay-region diol epoxides (ultimate mutagens and carcinogens) and their closely related optically active but biologically less active or inactive S,R,R,S enantiomers from several polycyclic and azapolycyclic aromatic hydrocarbons as probes for identifying cellular targets that are important for mutagenesis and carcinogenesis. We will determine the effects of optically active bay-region diol epoxide enantiomers on DNA base sequences in the coding region of the endogenous hypoxanthine phosphoribosyltransferase (HPRT) gene of Chinese hamster V-79 cells. We will also evaluate the mechanisms and possible in vivo significance of our recent observation of dose-dependent differences in the profile of mutations for an R,S,S,R bay-region diol epoxide in V-79 cells. We will determine whether the kinds of mutations that occur in the p53 and ras genes in tumors from animals the receive a high dose of the diol epoxide are the same or different from the mutations that occur in tumors from animals that receive a low dose of the carcinogen. An important goal of our research is to compare the mutation profiles of optically pure R,S,S,R bay-region diol epoxides in V-79 cells in vitro with the mutation profiles of these compounds in vivo. (3) inhibitory effects of naturally occurring dietary constituents and their derivatives on chemical carcinogenesis and ultraviolet light-induced carcinogenesis. In this research, we will attempt to identify potentially useful inhibitors of carcinogenesis and to use these inhibitors as tools for better understanding athe carcinogenic process. We will evaluate (a) potential inhibitory effects of curcumin, carnosol, ursolic acid, rosemary, tea and other dietary plant substances on chemical carcinogenesis and ultraviolet light-induced carcinogenesis, (b) potential inhibitory and/or stimulatory effects of 1alpha, 25-dihydroxyvitamin D3 on chemical carcinogenesis and ultraviolet light-induced carcinogenesis and (c) effects of chemopreventive substances on the growth and progression of skin papillomas. Possible mechanisms of action will be evaluated.