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可能有助于癌症生存的环境因素，如营养素。癌症患者的最佳维生素营养状况尚未得到很好的确定，维生素在预防临床上明显的癌症复发中的作用尚未得到广泛评估。我们的初步数据提供的证据表明，维生素叶酸的快速消耗与培养的人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抗性的假设。我们假设，根据我们的初步数据，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预防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，我们将通过评估叶酸补充剂对通常与耐药性发展相关的代谢物水平以及对与耐药性发展相关的基因表达的影响，试图确定叶酸补充剂降低耐药性的机制。 如果我们的研究成功，将为旨在评估维生素状况对癌症患者化疗抵抗力的影响的临床试验奠定基础。如果最终发现维生素补充剂可以降低对化疗药物的耐药性，那么一种简单而廉价的方法可以至少部分地预防限制化疗有效性的耐药性。

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.