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

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。确定安全和实用的预防药物应有助于控制。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，如果损伤没有得到修复，可能会导致肿瘤的发展。这项研究将首先确定预防药物（类似阿司匹林的药物、鱼油和抗氧化剂）调节DNA损伤的能力，然后检查这些药物联合使用的效果。它将最终确定药物的能力，或药物的组合，以防止发展结肠直肠癌使用两种动物模型。通过这种策略预防人类结直肠癌应该是可行的。首先，有证据表明DNA损伤在肿瘤发生中起重要作用。其次，DNA损伤、修复和移除的外源性调控似乎是可能的。流行病学研究表明，30-70%的癌症可以通过适当调整饮食（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）来预防。第三，预防战略可能是可行的。在人口层面上，它们需要在饮食生活方式的背景下是安全和可控的，但这可以通过一系列食品技术的发展来实现。在高危人群中，通过医患接触，个性化预防策略变得可行。本研究的重点是在肿瘤发展的早期阶段DNA损伤的调节及其修复和去除。该研究将提供信息，如果预防药物，单独或联合，提供一个有希望的策略，通过减少基因损伤结肠直肠癌。他们还可能发现新的生物标记物，便于在人类身上进行测试。

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.