Prevention of Lung Tumors by Agents using Concurrent and Sequential Treatment

描述(由申请人提供)：需要预防肺癌的化学预防药物。我们提出了五个目标：具体目标1：证明联合使用化学预防药物比单独使用单独作用的药物在预防肺癌方面具有更好的效果。具体目标2：确定化学预防药物同时治疗与序贯治疗的相对疗效。具体目的3.通过MRI识别肿瘤，并选择具有不同生长特征的肿瘤，以确定肺肿瘤的生长与基因表达之间的关联。具体目标4：确定以下基因的mRNA表达：i)随着肺癌的生长速度而改变；ii)被化学预防药物改变，与其预防肿瘤和减缓其生长的能力有关；以及iii)通过组合改变，即同时和连续给药，以确定这些药物如何相互作用来调节基因的表达。具体目的5.使用细胞培养模型来支持、确认和增加对化学预防药物之间相互作用的体内研究结果的信心。NNK将诱发肺癌，一周后(第4周)，小鼠将接受贝克沙罗汀、SAHA、舒林酸或这些药物的二元组合。将有两个疗程：4-28周和28-50周。在第二个治疗期(28-50周)，一些小鼠将继续接受与第一个治疗期相同的制剂，而其他小鼠将接受不同的制剂(以确定两种制剂顺序治疗的效果)或对照饮食(第4-28周)。只在第一个治疗期内接受药物治疗并随后接受对照饮食的小鼠将被用于确定是否需要继续治疗，而在第一个治疗期内接受对照饮食并在第二个治疗期内接受化学预防性药物治疗的小鼠将被用于确定晚期干预措施防止癌症进展的疗效。一些对照组和贝沙罗汀治疗组的小鼠将在第20、28、38和48周通过核磁共振进行监测，以识别不同生长速度的肿瘤。总而言之，我们的预期结果是确定：i)由贝沙罗汀、SAHA、舒林酸组成的组合在同时和连续治疗下的化学预防效果，以及ii)这三种药物及其组合对mRNA表达的调节。公共卫生相关性：有必要证明化学预防药物，包括药物的组合，将防止肺癌的发展。将评估联合使用化学预防药物，即同时给药和顺序给药，以确定哪种药物在预防肺癌方面效果更好。将研究化学预防药物和药物组合对基因mRNA表达的调节，以加快药物和治疗方案的开发。

DESCRIPTION (provided by applicant): There is a need for chemopreventive agents that prevent lung cancer. We propose five Aims: Specific Aim 1: Demonstrate that the combined use of chemopreventive agents has greater efficacy in preventing lung tumors than the individual agents acting alone. Specific Aim 2: Determine the relative efficacy of concurrent versus sequential treatment with chemopreventive agents. Specific Aim 3. Identify tumors by MRI and select those with differing growth characteristics that will be used to determine the association between the growth of lung tumors and mRNA expression of genes. Specific Aim 4: Determine mRNA expression of genes that are: i) altered with the growth rate of lung tumors; ii) altered by chemopreventive agents in association with their ability to prevent tumors and to slow their growth; and iii) altered by combinations i.e., concurrent and sequential administration of agents to determine how the agents interact to modulate the expression of genes. Specific Aim 5. Use a cell culture model to support, confirm, and increase the confidence in the results of the in vivo study of the interaction between the chemopreventive agents. Lung tumors will be induced by NNK and one week later (Week 4), the mice will receive bexarotene, SAHA, sulindac or binary combinations of the agents. There will be two treatment periods; Weeks 4-28, and Weeks 28-50. In the second treatment period (Weeks 28-50), some mice will continue to receive the same agent as in the First Treatment Period, while others will receive either a different agent (to determine the efficacy of sequential treatment by two agents) or the Control Diet (Week 4-28). Mice that receive an agent only during the First Treatment Period followed by the Control Diet will be used to determine the need for continued treatment, while mice that receive the Control Diet during the first Treatment Period and followed in the Second Treatment Period by a chemopreventive agent will be used to determine the efficacy of late intervention to prevent the progression to cancer. Some Control and bexarotene-treated mice will be monitored by MRI at Weeks 20, 28, 38 and 48 to identify tumors with differing growth rates. In summary, our expected outcomes are determination of: i) the chemopreventive efficacy of combinations consisting of bexarotene, SAHA, sulindac using both concurrent and sequential treatment, and ii) the modulation of mRNA expression by the three agents and their combinations. PUBLIC HEALTH RELEVANCE: There is a need to demonstrate that chemopreventive agents, including combinations of agents, will prevent the development of lung cancer. The combined use of chemopreventive agents i.e., simultaneous and sequential administration, will be evaluated to determine which has the greater efficacy in preventing lung cancer. The modulation of mRNA expression of genes by chemopreventive agents and combinations of agents will be investigated that could be used to expedite the development of agents and treatment regimens