Combined Chemoprevention in Beta-Catenin Mutant Mice

β-连环蛋白突变小鼠的联合化学预防

• 批准号: 6617694
• 负责人: GAYLE A ORNER
• 金额: $ 7.08万
• 依托单位: OREGON 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: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617694
• 关键词: SDS polyacrylamide gel electrophoresis; apoptosis; cadherins; cell proliferation; chemoprevention; colon polyp; colorectal neoplasms; combination chemotherapy; gastrointestinal disorder chemotherapy; genetically modified animals; immunoprecipitation; laboratory mouse; nonsteroidal antiinflammatory agent; nutrition aspect of cancer; nutrition related tag; tea; transfection; western blottings

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer deaths in the United States. According to the American Cancer Society, more than 130,000 Americans will be diagnosed with cancer of the colon or rectum this year. Fortunately researchers are making extraordinary progress in the development and/or identification of agents that may delay or prevent colorectal cancer. These include pharmaceuticals such as the non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are effective at preventing polyp formation in familial adenomatous polyposis (FAP) patients having a genetic predisposition to cancer. Epidemiological evidence suggests that long-term NSAID use is associated with a decreased risk of colon cancer in non-familial colon cancer as well. However, NSAIDs can produce serious side effects, including gastrointestinal bleeding and even death. One strategy to minimize toxicity of NSAIDs is to use very low doses in combination with other agents having complementary modes of action. Tea prevents intestinal and/or colorectal cancer in a variety of animal models. A combination of tea plus the NSAID sulindac was recently shown to be highly effective at preventing the formation of tumors in Apc[min] mice. These mice have a mutation in Apc (same gene altered in FAP) and, like humans with FAP, are genetically predisposed to develop large numbers of intestinal adenomas at an early age. This suggests that a combination of tea plus sulindac may be of benefit in treating humans with FAP. However, the majority of human colon cancers are not hereditary; instead their cause is unknown, but may be due to interaction of environmental and genetic factors. The A33[delta-N-beta-cat] mouse is an innovative new animal model that may be particularly appropriate as a mimic for non-familial colorectal cancer. A33[delta-N-beta-cat] mice express an oncogenic form of beta-catenin in their intestines. The A33[delta-N-beta-cat] mice do not develop multiple intestinal tumors at an early age like Apc[min] mice, but are highly susceptible to chemically induced colon cancer. The proposed studies are the first chemoprevention studies to be conducted in A33[delta-N-beta-cat] mice. These studies will examine the combined benefits of tea plus low-dose sulindac as preventive agents towards colon cancer. This research will provide valuable information on how dietary factors and pharmaceuticals interact in the prevention of intestinal cancer, and may also expedite future cancer prevention research through further validation of the A33[delta-N-beta-cat] mouse model.

描述（由申请人提供）： 结直肠癌是美国癌症死亡的第二大原因。根据美国癌症学会的数据，今年将有13万多名美国人被诊断出患有结肠或直肠癌。幸运的是，研究人员在开发和/或鉴定可能延迟或预防大肠癌的药物方面取得了非凡的进步。这些包括药物，例如非甾体类抗炎药（NSAID）。 NSAID可有效防止在具有遗传易感性癌症的家族性腺瘤性息肉病（FAP）患者中形成息肉。流行病学证据表明，长期的NSAID使用与非家庭结肠癌的结肠癌风险降低有关。但是，NSAID可以产生严重的副作用，包括胃肠道出血甚至死亡。最小化NSAID毒性的一种策略是将非常低剂量与其他具有互补作用方式的药物结合使用。茶可防止各种动物模型中的肠道和/或大肠癌。茶加上NSAID Sulindac的组合最近被证明在防止APC [min]小鼠中形成肿瘤方面非常有效。这些小鼠在APC中具有突变（在FAP中改变了基因），并且像患有FAP的人一样，在遗传上倾向于在幼年时期发展大量肠道腺瘤。这表明，茶加苏莱达克的组合可能在用FAP治疗人类方面有益。但是，大多数人类结肠癌不是遗传性的。相反，它们的原因是未知的，但可能是由于环境和遗传因素的相互作用。 A33 [delta-n-beta-cat]小鼠是一种创新的新动物模型，可能特别适合于非家族结直肠癌。 A33 [delta-n-beta-cat]小鼠在其肠道中表达β-catenin的致癌形式。 A33 [delta-n-beta-cat]小鼠在早期就不会像APC [min]小鼠那样出现多个肠道肿瘤，但非常容易受到化学诱导的结肠癌的影响。拟议的研究是在A33 [delta-n-beta-cat]小鼠中进行的首次化学预防研究。这些研究将研究茶的综合益处，而低剂量的硫酸作为结肠癌的预防剂。这项研究将提供有关饮食因素和药物如何在预防肠道癌中相互作用的宝贵信息，并且还可以通过进一步验证A33 [delta-n-beta-cat]小鼠模型来加快未来的癌症预防研究。