Prevention of Esophageal Cancer with Berries

用浆果预防食道癌

• 批准号: 6925381
• 负责人: Gary Stoner
• 金额: $ 46.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925381
• 关键词: apoptosis; biological signal transduction; cancer prevention; carcinogenesis; cell proliferation; cell transformation; chemoprevention; combination chemotherapy; cysteine endopeptidases; cytochrome P450; cytochrome c; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; esophagus neoplasm; fruit; high performance liquid chromatography; isothiocyanates; laboratory rat; neoplasm /cancer pharmacology; neoplastic process; nitrosamines; nutrition aspect of cancer; polymerase chain reaction; squamous cell carcinoma; toxicology

DESCRIPTION (provided by applicant): Squamous cell carcinoma (SCC) of the human esophagus is a multifactorial disease with a significant behavorial component. Primary chemoprevention has emerged as a potentially viable approach to reduce the risk of esophageal cancer in high-risk individuals. N-Nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F-344 rat has proven to be a useful animal model for investigations of SCC of the esophagus. For the last fifteen years, the goal of our laboratory has been to identify effective chemopreventive agents for the disease using this animal model. Our previous work (5-10 years ago) with isothiocyanates demonstrated that phenethyl isothiocyanate (PEITC) and 3- phenylpropyl isothiocyanate (PPITC) are exquisitely potent inhibitors of tumor initiation (i.e., blocking agents) in the rat esophagus. However, at that time, there were few, if any, demonstrable inhibitors of the promotion/progression stages of rat esophageal tumorigenesis (i.e., suppressing agents). Thus, the past five years have been largely devoted to the discovery of non-isothiocyanate chemopreventive agents in this model, particularly the identification of potent suppressing agents. We have found that lyophilized black raspberries (BRB) act as an effective chemopreventive agent in the model, and that BRB exhibit both blocking and suppressing activity. Our preliminary data indicate that BRB exhibit blocking activity by influencing the metabolism of NMBA, thus reducing the levels of NMBA-induced damage in esophageal DNA. At least one mechanism by which BRB exhibit suppressing activity is by reducing the growth rate of preneoplastic esophageal epithelial cells. The ultimate goals of the proposed project are to develop an improved understanding of the mechanism(s) by which BRB exhibit blocking and suppressing activity in the rat esophagus and to develop an effective "cocktail" of chemopreventive agents for later use in the primary chemoprevention of human esophageal SCC. Accordingly, we propose the following Specific Aims for our future investigations: (1) to identify the active inhibitory components of lyophilized BRB; (2) to determine the mechanistic basis of the anti-initiating effects of lyophilized BRB; (3) to investigate the mechanistic basis of the suppressing effects of lyophilized BRB; (4) to test the chemopreventive efficacies of specific compounds isolated from lyophilized BRB or specific BRB extracts; and (5) to evaluate the combined effects of BRB isolates and isothiocyanates on rat esophageal tumorigenesis.

描述（由申请人提供）：人类食管的鳞状细胞癌（SCC）是一种多因素疾病，具有重要的遗殖成分。原发性预防已成为降低高危个体食管癌风险的潜在可行方法。 N-亚硝基甲基苯胺（NMBA）诱导的F-344大鼠食管肿瘤发生已被证明是研究食道SCC的有用动物模型。在过去的十五年中，我们实验室的目标是使用该动物模型鉴定有效的化学预防剂。我们先前使用异硫氰酸酯的工作（5-10年前）表明，异硫氰酸苯基（PEITC）和3-苯基丙基异硫氰酸酯（PPITC）是对大鼠食管中肿瘤起始（即阻断剂）的明显有效抑制剂。但是，当时，大鼠食管肿瘤发生的促进/进展阶段（即抑制剂）的促进/进展阶段的抑制很少（如果有的话）。因此，在过去的五年中，在该模型中发现了非异硫氰酸酯化学预防剂，特别是鉴定有效抑制剂。我们发现，冻干的黑色覆盆子（BRB）在模型中充当了一种有效的化学预防剂，并且BRB表现出阻塞和抑制活性。我们的初步数据表明，BRB通过影响NMBA的代谢而表现出阻塞活性，从而降低了NMBA诱导的食管DNA损伤水平。 BRB表现出抑制活性的至少一种机制是通过降低产质食管上皮细胞的生长速率。拟议项目的最终目标是对BRB在大鼠食道中表现出阻塞和抑制活性的机制有了改进的理解，并开发了化学预防剂的有效“鸡尾酒”，以便以后在人类食管SCC的主要化学预防中使用。因此，我们提出了以下对未来研究的特定目标：（1）确定冻干BRB的活跃抑制成分； （2）确定冻干BRB的抗发射作用的机械基础； （3）研究冻干BRB抑制作用的机理基础； （4）测试从冻干BRB或特定BRB提取物中分离出的特定化合物的化学预防效应； （5）评估BRB分离株和异硫氰酸盐对大鼠食管肿瘤发生的综合作用。