Vitamins and Prevention of Cancer Progression

描述(由申请人提供)： 对预防癌症进展的目标的一个贡献是确定环境因素，例如可能有助于癌症存活率的营养物质。癌症患者的最佳维生素营养尚未得到很好的确定，维生素在预防临床明确的癌症复发中的作用也没有得到广泛的评价。我们的初步数据提供了证据，证明维生素叶酸的快速消耗与培养的人类肺癌和卵巢细胞对化疗药物顺铂的耐药性增加有关。该项目的总体目标是检验叶酸影响肺癌细胞对顺铂作用的耐药性的假说。根据我们的初步数据，我们推测，叶酸将防止顺铂的内在和获得性耐药。为了验证这一假设，我们提出了以下两个具体目标： 具体目标1：确定改变叶酸浓度是否可以防止或逆转对化疗药物顺铂的耐药性。 具体目标2：评估叶酸改变顺铂耐药性的机制。 在第一个具体目标中，我们将评估补充叶酸是否会降低顺铂的耐药性。我们将在几种肺癌细胞系中测试叶酸和顺铂。在具体目标2中，我们将试图通过评估叶酸补充对通常与耐药性发生相关的代谢物水平以及与耐药性发生相关的基因表达的影响来确定叶酸补充降低耐药性的机制。 如果我们的研究成功，旨在评估维生素状况对癌症患者化疗耐药性影响的临床试验的理论基础将被确立。如果补充维生素最终被发现可以减少对化疗药物的耐药性，那么一种简单而廉价的方法将实现，至少在一定程度上防止限制化疗效果的耐药性。

DESCRIPTION (provided by applicant): One contribution toward the goal preventing cancer progression would be to identify environmental factors such as nutrients that may contribute to cancer survivorship. The optimal vitamin nutriture of cancer patients is not well established, and the role of vitamins in preventing the recurrence of clinically overt cancer has not been widely evaluated. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer and ovarian cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influences the resistance in lung cancer cells to the action of cisplatin. We hypothesize, based on our preliminary data, that folate will prevent intrinsic and acquired resistance to cisplatin. To test this hypothesis, we propose the following two specific aims: Specific Aim 1: To determine whether altered folic acid concentrations can prevent or reverse resistance to the chemotherapeutic agent cisplatin. Specific Aim 2: To evaluate the mechanisms by which folic acid alters resistance to cisplatin. In the first specific aim, we will evaluate whether supplementation with folic acid decreases the resistance to cisplatin. We will test folate and cisplatin in several lung cancer cell lines. In Specific Aim 2, we will attempt to determine the mechanism by which folate supplementation decreases resistance by evaluating the effect of folate supplementation on levels of metabolites commonly associated with the development of resistance, and on expression of genes associated with development of resistance. If our studies are successful, a rationale for clinical trials aimed at evaluating the influence of vitamin status on resistance to chemotherapy in cancer patients would be established. If vitamin supplementation is ultimately found to decrease resistance to chemotherapeutic agents, then a simple and inexpensive approach to prevent, at least in part, the resistance that limits the effectiveness of chemotherapy will be realized.