Defining the promoting effect of folate on colorectal cancer in a novel animal mo

描述(由申请人提供)：在美国和其他国家，什么是健康的维生素B-叶酸的饮食摄入量是当今备受关注的问题。尽管适量的叶酸摄入可以预防结直肠癌，但越来越多的证据表明，在那些存在癌前病变或癌病变的人中，叶酸摄入量过多可能会导致肿瘤发生的矛盾加速。美国人的饮食中有许多叶酸来源，可以补充食物中的天然含量：自愿强化食品、维生素补充剂和强制性强化。根本的问题是，这些来源加在一起是否足以产生叶酸的促癌作用；这是一个严重的问题，已经有来自几个临床前和临床研究的支持证据。由于伦理和时间的限制，这一困境不能仅靠人类研究来解决。与这一现实相一致的是最近一次关于这一主题的国际会议的结论，其中包括高度优先的建议，即需要在适当的动物模型中探讨这一问题。因此，这项提议的总体目标是在一个高度创新和强大的动物模型的背景下回答这些问题。这种新的结直肠癌发生的动物模型，GEM-1，允许人们在几个月的时间内监测体内结肠癌的发展。这将使我们能够确定关键参数，如饮食叶酸具有促进作用的剂量阈值，并开发出定义这种关系的数学模型。我们建议的研究将：1)表征GEM-1模型对超生理学剂量的饮食叶酸的反应与癌症促进，2)确定超生理学叶酸摄入与加速肿瘤形成之间的剂量-反应关系的量化性质，3)确定超生理学数量的天然形式的维生素5-甲基四氢叶酸是否缺乏观察到的合成形式叶酸的促癌作用，以及4)提供证据，证明过量的叶酸通过为DNA合成提供大量的限速底物胸苷来推动癌症的发生。 与公共健康相关：在美国和其他国家，关于什么是健康的B-维生素叶酸的饮食摄入量存在着巨大的争论，因为这种维生素的许多来源已经被引入食物流，而且越来越多的证据表明，过量的维生素可能会增加患结直肠癌的风险。关于癌症可能的促进作用的现有数据相当模棱两可，但潜在的影响非常大，这使这成为一个特别紧迫的公共卫生问题，需要紧急解决。这项申请中提出的研究将在一种新颖且特别适合的动物模型中进行，并将提供重要的答案，即叶酸的摄入是否有助于优化人口的一部分人的健康，是否会对社会的其他部分构成潜在风险。

DESCRIPTION (provided by applicant): Of great contemporary concern in the U.S., as well as in other countries, is the question of what constitutes a healthful dietary intake of the B-vitamin, folate. Although adequate amounts of folate intake protect against colorectal cancer, accumulating evidence indicates that overly abundant quantities among those who harbor pre-cancerous or cancerous lesions may produce a paradoxical acceleration of tumorigenesis. There are many sources of folic acid in the american diet that supplement the quantities naturally present in foods: voluntarily-fortified foods, vitamin supplements and mandatory fortification. The seminal question is whether these sources are collectively sufficient to produce the cancer-promoting effect of folate; a grave concern for which there is already supportive evidence from several pre-clinical and clinical studies. Due to ethical and chronological constraints, this dilemma cannot be resolved by human studies alone. Consistent with this reality are the conclusions of a recent international conference on the topic, which included among the high priority recommendations the need to pursue the issue in appropriate animal models. The overall goal of this proposal, therefore, is to answer these questions within the context of a highly innovative and powerful animal model. This novel animal model of colorectal carcinogenesis, GEM-1, allows one to monitor development of colonic neoplasms in vivo over a period of several months. This will enable us to determine critical parameters such as the threshold of dose at which dietary folate has a promotional effect and to develop a mathematical model that defines the relationship. Our proposed studies will: 1) characterize the GEM-1 model's response to supraphysiological quantities of dietary folic acid in regard to cancer promotion, 2) define the quantitative nature of the dose-response relationship between supraphysiological folic acid intake and acceleration of tumorigenesis, 3) determine whether delivery of supraphysiological quantities of a natural form of the vitamin, 5-methyltetrahydrofolate, lacks the cancer-promoting effects observed with the synthetic form, folic acid, and 4) provide evidence that the molecular pathway by which excess folic acid is driving carcinogenesis is by providing abundant quantities of the rate-limiting substrate for DNA synthesis, thymidine. PUBLIC HEALTH RELEVANCE: There is great debate in the U.S. and in other countries as to what constitutes a healthful dietary intake of the B-vitamin, folate, because many sources of the vitamin have been introduced into the food stream and there is accumulating evidence to suggest that overly abundant quantities of the vitamin may promote the risk of colorectal cancer. The existing data concerning the possible promotion of cancer is rather equivocal, and yet the potential ramifications are very great, making this a particularly pressing public health issue that needs to be addressed with some urgency. The studies proposed in this application will be conducted in a novel and particularly well-suited animal model and will provide important answers as to whether the intake of folate that is helping optimize health for one segment of the population might be presenting potential risks to other segments of the society.