Regulation of mutational load by chemopreventive agents and implications for molecular pathogenesis of colorectal cancer

化学预防剂对突变负荷的调节及其对结直肠癌分子发病机制的影响

• 批准号: nhmrc : 324719
• 负责人: Dr Richard Le Leu
• 金额: $ 28.26万
• 依托单位: Flinders University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/regulation-mutational-load-colorectal-cancer/77051
• 关键词: Regulation; mutational; load; chemopreventive; agents

In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous (internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour development if the damage is not repaired. This study will first identify the ability of preventive agents (aspirin-like drugs, fish oil, and antioxidants) to regulate DNA damage, then examine the effect of combination of the agents. It will finally determine the ability of agents, or combination of agents, to prevent development of colorectal cancer using two animal models. Prevention of human CRC by such a strategy should be feasible. First, evidence indicates that DNA damage is important in tumour initiation. Second, exogenous regulation of DNA damage, repair and removal seems possible. Epidemiological studies have suggested that that 30-70% of cancer can potentially be prevented with proper adjustment of diets (fat, fibre, resistant starch) and supplements of drugs (NSAIDs) or antioxidants (Vitamin, Selenium). Third, preventive strategies are likely to be feasible. At the population level, they would need to be safe and manageable in the context of dietary lifestyle, but this can be achieved through a range of food technology developments. In individuals at high risk, personalised preventive strategies become feasible through doctor-patient contact. This study focuses on regulation of DNA damage, and its repair and removal during the early stage of tumour development. The study will provide information if preventive agents, alone or in combination, provide a promising strategy for colorectal cancer through reduction of genetic damage. They might also identify new biomarkers that facilitate testing in humans.

在澳大利亚，结直肠癌是癌症死亡的第二大常见原因，但结直肠癌的发病率和死亡率目前尚未得到控制。确定安全实用的预防剂应有助于控制。越来越多的证据表明结直肠癌与内源性（内部）和外源性（外部）因素有关。它们会对 DNA 造成损伤，如果损伤得不到修复，可能会导致肿瘤的发生。这项研究将首先确定预防药物（阿司匹林类药物、鱼油和抗氧化剂）调节 DNA 损伤的能力，然后检查这些药物组合的效果。最终将使用两种动物模型确定药物或药物组合预防结直肠癌发展的能力。通过这样的策略预防人类结直肠癌应该是可行的。首先，有证据表明 DNA 损伤在肿瘤发生中很重要。其次，DNA损伤、修复和去除的外源调节似乎是可能的。流行病学研究表明，通过适当调整饮食（脂肪、纤维、抗性淀粉）和补充药物（非甾体抗炎药）或抗氧化剂（维生素、硒），可以预防 30-70% 的癌症。第三，预防策略可能是可行的。在人口层面，他们需要在饮食生活方式的背景下安全且易于管理，但这可以通过一系列食品技术的发展来实现。对于高危个体，通过医患接触，个性化的预防策略变得可行。本研究重点关注肿瘤发展早期阶段 DNA 损伤的调节及其修复和去除。该研究将提供信息，说明预防药物单独或联合使用是否可以通过减少遗传损伤为结直肠癌提供有前景的策略。他们还可能识别出有助于人体测试的新生物标志物。