CANCER CAUSE AND PREVENTION RESEARCH

拟议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和 为预防癌症提供了新的方法。建议数 研究关注的是： (1)最终致突变和致癌代谢产物的鉴定 多环芳烃及其相关的含氮化合物 我们环境中的杂环烃。这样做的一个重要目的是 研究是为了加强我们对未被探索的方面的理解 环境二醇环氧化物的构效关系 重要的多环芳烃及其相关的氮- 含有杂环的。 (2)光学活性致癌和致突变的机制 R，S，S，R湾区多环芳烃二醇环氧化物和 它们的含氮类似物。在本研究中，我们将使用R、S、S、R 湾区二元醇环氧化物(终极致突变物和致癌物)及其 密切相关的光学活性，但生物学上不太活跃或不活跃 几种多环和氮杂多环芳香族化合物的S、R、R、S对映体 碳氢化合物作为识别重要细胞靶标的探针 用于诱变和致癌。我们将确定 DNA碱基序列上具有光学活性的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细胞的磷酸核糖转移酶基因。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的轮廓 V-79细胞中R、S、S、R湾区二醇环氧化物突变的研究 我们将确定发生在P53和P53中的各种突变 接受高剂量二醇的动物肿瘤中的RAS基因 环氧化物与肿瘤中发生的突变相同或不同 来自接受低剂量致癌物质的动物。一个重要的目标 我们研究的重点是比较光学纯种的突变图谱 R，S，S，R湾区二醇环氧化物突变对V-79细胞的影响 这些化合物在体内的分布情况。 (3)天然饮食成分的抑制作用 其衍生物对化学致癌和紫外光诱导的影响 致癌。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 以便更好地了解致癌过程。我们将评估(A) 姜黄素、卡诺索尔、熊果酸、迷迭香、 茶和其他食用植物物质对化学致癌和 紫外光诱导致癌，(B)潜在的抑制和/或 1α，25-二羟基维生素D3对化学物质的刺激作用 致癌和紫外光致癌及(C)效应 化学预防物质对皮肤生长发育的影响 乳头状瘤。将对可能的行动机制进行评估。

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.