Cancer CAM Vitamins and Chemotherapy Resistance

描述（由申请人提供）：国家癌症研究所的重点仍然是提高生存率和提高癌症幸存者的生活质量。实现这一目标的一个贡献将是确定有助于癌症生存的环境因素，包括通常建议在癌症补充和替代医学（CAM）中补充的营养因素。癌症患者的最佳维生素营养状况尚未完全确定。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癌细胞对用于癌症化疗的药剂的作用的抗性的假设。基于我们的初步数据，我们假设叶酸可以预防肺癌和卵巢癌化疗中常用的抗癌药物的内在和获得性耐药性。为了验证这一假设，我们提出了以下三个具体目标： 具体目标1：确定高剂量叶酸是否可以抑制顺铂耐药性的发展。具体目标二：评估叶酸水平和DNA甲基化在顺铂耐药发展过程中作为维生素状态的函数的变化。具体目标3：评估高剂量叶酸改变顺铂耐药性的机制。 这些研究将告诉我们，用于癌症正分子医学治疗和癌症CAM的维生素是否能有效预防对常用癌症化疗药物产生耐药性。我们将比较非常高的叶酸浓度，类似于CAM治疗方案中可能使用的叶酸，叶酸水平不足，正常和中度升高，以便清楚地了解非常高剂量的叶酸相对于常规临床方案中可能在癌症患者中测试的中等剂量的有效性。

DESCRIPTION (provided by applicant): The focus at the National Cancer Institute continues to be on increasing survivorship and on enhancing the quality of life for cancer survivors. One contribution toward this goal would be to identify environmental factors that contribute to cancer survivorship, including nutritional factors that are commonly recommended for supplementation in cancer complementary and alternative medicine (CAM). The optimal vitamin nutriture of cancer patients is not well established. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influence the resistance in cancer cells to the action of agents used for cancer chemotherapy. We hypothesize, based on our preliminary data, that folic acid will prevent intrinsic and acquired resistance to anticancer agents commonly used in lung and ovarian cancer chemotherapy. To test this hypothesis, we propose the following three Specific Aims: Specific Aim 1: To determine whether high doses of folic acid can inhibit development of resistance to cisplatin. Specific Aim 2: To evaluate changes in folic acid levels and DNA methylation as a function of vitamin status during the development of resistance to cisplatin. Specific Aim 3: To evaluate the mechanisms by which high doses of folic acid alter resistance to cisplatin. These studies will tell us whether a vitamin used in cancer orthomolecular medical therapies and in cancer CAM is effective in preventing the development of resistance to commonly used cancer chemotherapeutic agents. We will compare very high folic acid concentrations, similar to what might be used in CAM treatment protocols, with deficient, normal and moderately elevated levels of folic acid, in order to get a clear picture of the effectiveness of very high doses of folic acid relative to the modest doses that would likely be tested in cancer patients in conventional clinical protocols.