CANCER CHEMOPREVENTIVE AGENTS ON DNA ADDUCT BY DIETARY PROSTATE CARCINOGEN PHIP

针对膳食前列腺癌 PHIP DNA 加合物的癌症化学预防剂

• 批准号: 7358997
• 负责人: Kenneth W. Turteltaub
• 金额: $ 1.62万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358997
• 关键词: CANCER; CHEMOPREVENTIVE; AGENTS; DNA; ADDUCT

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer is a leading cause of cancer death in men, yet the major factors in the development of this disease remain largely unidentified. Studies analyzing cancer incidence in populations have indicated that certain dietary constituents, such as meat, enhance prostate cancer risk. In contrast, tomatoes, green vegetables, vitamin E and the mineral selenium reduce risk. Although a diet high in fruits and vegetables and low in meat appears beneficial, there is little direct evidence to support these findings or to explain a role for dietary factors in the development of prostate cancer. Current animal models used to assess the biological effects of potential carcinogens and the effectiveness of chemopreventive agents typically employ high carcinogen doses, which are of little biological relevance to the low levels encountered in the diet. However, investigations employing carcinogen doses likely to be encountered in the environment are difficult and require the use of very sensitive assays. Accelerator mass spectrometry is a highly sensitive technique capable of measuring trace amounts of chemicals. AMS will be used to determine if a dietary carcinogen formed in meat during cooking is a prostate cancer risk factor at dietary-levels of exposure. PhIP has been shown to cause DNA damage (an initial step in the development of cancer) and induce prostate tumors in rats following high doses. These observations, coupled with the enhanced risk of prostate cancer from the consumption of meat, further emphasizes the potential role for PhIP in the development of prostate cancer in humans. The amount of DNA damage in the prostate of rats following exposure to dietary-relevant doses of PhIP has been determined by AMS. We then assessed the effectiveness of the chemopreventive agents lycopene (a component of tomatoes), chlorophyllin, the isothiocyanate PEITC and genistein in reducing the amount of DNA damage. Consequently, the work determined that a carcinogen in meat may cause prostate cancer at low doses and has helped identify effective chemoprevention strategies. A poster presentation on the work to date has been given at several venues: International research Conference on Food, Nutrition, and Cancer in Washington DC, July 14 and 15, 2005; The 11th Annual Cancer Research Symposium at UC Davis, Oct 27-28, 2005; and at the LLNL at the Bio Symposium Dec 8 and 9, 2005.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。前列腺癌是男性癌症死亡的主要原因，然而，这种疾病发展的主要因素在很大程度上仍未确定。分析人群中癌症发病率的研究表明，某些饮食成分，如肉类，会增加患前列腺癌的风险。相反，西红柿、绿色蔬菜、维生素E和矿物质硒可以降低风险。虽然多吃水果和蔬菜，少吃肉类的饮食似乎是有益的，但几乎没有直接证据支持这些发现，也没有直接证据解释饮食因素在前列腺癌发展中的作用。目前用于评估潜在致癌物的生物效应和化学预防剂有效性的动物模型通常采用高致癌物剂量，这与饮食中低水平的致癌物剂量几乎没有生物学相关性。然而，使用在环境中可能遇到的致癌物剂量进行调查是困难的，需要使用非常敏感的测定方法。加速器质谱法是一种高度灵敏的技术，能够测量微量的化学物质。AMS将用于确定肉类在烹饪过程中形成的膳食致癌物在饮食暴露水平上是否是前列腺癌的风险因素。PhIP已被证明会导致DNA损伤（癌症发展的第一步），并在大鼠中引起前列腺肿瘤。这些观察结果，加上食用肉类会增加患前列腺癌的风险，进一步强调了PhIP在人类前列腺癌发展中的潜在作用。暴露于饮食相关剂量的PhIP后，大鼠前列腺DNA损伤量已由AMS测定。然后，我们评估了化学预防剂番茄红素（番茄的一种成分）、叶绿素、异硫氰酸酯PEITC和染料木素在减少DNA损伤量方面的有效性。因此，这项工作确定肉类中的致癌物在低剂量下可能导致前列腺癌，并有助于确定有效的化学预防策略。迄今为止的工作已在几个地点进行了海报展示：2005年7月14日和15日在华盛顿特区举行的国际食品、营养和癌症研究会议；2005年10月27-28日在加州大学戴维斯分校举行的第11届年度癌症研究研讨会；2005年12月8日和9日在LLNL的生物研讨会上。