Colon Cancer Chemoprevention

结肠癌化学预防

• 批准号: 8532489
• 负责人: SHARAD KHARE
• 金额: $ 7.15万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532489
• 关键词: Colon; Cancer; Chemoprevention

DESCRIPTION (provided by applicant): We have previously demonstrated that supplemental dietary Ursodeoxycholic Acid (UDCA) inhibited the development of azoxymethane-induced rat colonic tumors. To examine the mechanisms by which UDCA causes anticarcinogenic effects, studies in this proposal demonstrated that UDCA increased RasGAP activity and generated caspase-3 dependent RasGAP -N and -C terminal fragments. The important goal of this application is to determine whether RasGAP C-terminal fragment has a role in the inhibition of colon cancer. In cell culture studies we have demonstrated that RasGAP C-terminal fragment sensitizes colon cancer cells towards UDCA-induced apoptosis. To study tumor suppression by RasGAP C-terminal fragments, in vivo, we will utilize nude mouse model. This will be the first attempt to evaluate the anti-cancer activity of RasGAP C-terminal fragment in colon cancer. Colon cancer cells over-expressing RasGAP C-fragment protein will be injected into mice and tumor growth characteristics will be observed in the presence of UDCA. Further, we have also utilized an innovative technology in isolating RasGAP C-fragment protein attached to a HIV peptide, which permits its transport across cell membranes. To assess the therapeutic benefit, this protein will be injected directly in the tumor. Our rationale for these studies is that development of scientifically based evidence to support a preventive and therapeutic benefit of RasGAP C-terminal fragment would provide a foundation for human studies to test potential benefits in cancer patients and high risk individuals. It is hoped that the information gained by this proposal can be exploited and applied towards the design of a more effective inhibitor for colon cancer prevention and therapy.

描述（由申请人提供）： 我们以前已经证明，补充膳食熊去氧胆酸（UDCA）抑制氧化偶氮甲烷诱导的大鼠结肠肿瘤的发展。为了检查UDCA引起抗癌作用的机制，本提案中的研究表明，UDCA可增加RasGAP活性并产生半胱天冬酶-3依赖性RasGAP -N和-C末端片段。本申请的重要目标是确定RasGAP C末端片段是否在抑制结肠癌中具有作用。在细胞培养研究中，我们已经证明RasGAP C-末端片段使结肠癌细胞对UDCA诱导的凋亡敏感。为了研究RasGAP C-末端片段的体内肿瘤抑制，我们将利用裸鼠模型。这将是首次尝试评估RasGAP C端片段在结肠癌中的抗癌活性。将过表达RasGAP C片段蛋白的结肠癌细胞注射到小鼠体内，并在存在UDCA的情况下观察肿瘤生长特征。此外，我们还利用了一种创新技术来分离附着在HIV肽上的RasGAP C片段蛋白，该肽允许其跨细胞膜转运。为了评估治疗益处，将这种蛋白质直接注射到肿瘤中。我们进行这些研究的理由是，开发基于科学的证据来支持RasGAP C-末端片段的预防和治疗益处，将为人类研究提供基础，以测试癌症患者和高危个体的潜在益处。希望通过该建议获得的信息可以被开发和应用于设计更有效的结肠癌预防和治疗抑制剂。