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，当代非常关注的问题是什么构成健康的饮食摄入维生素b，叶酸。虽然足够的叶酸摄入量可以预防结直肠癌，但越来越多的证据表明，在那些有癌前病变或癌性病变的人群中，过量的叶酸可能会加速肿瘤的发生。在美国人的饮食中有许多叶酸的来源，可以补充食物中自然存在的叶酸：自愿强化食品，维生素补充剂和强制强化。重要的问题是，这些来源是否足以产生叶酸的促癌作用；一些临床前和临床研究已经提供了支持证据，这是一个严重的问题。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，其中包括需要在适当的动物模型中研究这一问题的高度优先建议。因此，本提案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。这种新型的结直肠癌动物模型GEM-1，可以在几个月的时间内监测结肠肿瘤在体内的发展。这将使我们能够确定关键参数，如膳食叶酸具有促进作用的剂量阈值，并建立定义这种关系的数学模型。我们建议的研究将：1)描述了gem1模型对超过生理量的膳食叶酸在促进癌症方面的反应，2)定义了超过生理量的叶酸摄入与肿瘤发生加速之间的剂量-反应关系的定量性质，3)确定了超过生理量的维生素5-甲基四氢叶酸的天然形式的递送是否缺乏与合成形式的叶酸观察到的促进癌症的作用。4)提供证据证明过量叶酸驱动癌变的分子途径是通过为DNA合成提供大量的限速底物胸腺嘧啶。

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.