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剂。我们提出五个目标：具体目标1：证明联合使用化学预防剂比单独使用化学预防剂在预防肺肿瘤方面具有更大的功效。具体目标2：确定化学预防药物同时与序贯治疗的相对疗效。具体目标3。通过MRI识别肿瘤，并选择具有不同生长特征的肿瘤，用于确定肺肿瘤生长与基因mRNA表达之间的相关性。具体目标4：确定以下基因的mRNA表达：i）随着肺肿瘤的生长速率而改变; ii）被化学预防剂改变，与其预防肿瘤和减缓其生长的能力相关;和iii）被组合改变，即，同时和顺序施用试剂以确定试剂如何相互作用以调节基因的表达。具体目标5.使用细胞培养模型来支持、确认和增加化学预防剂之间相互作用的体内研究结果的置信度。肺肿瘤将由NNK诱导，并且一周后（第4周），小鼠将接受贝沙罗汀、SAHA、舒林酸或药剂的二元组合。将有两个治疗期：第4-28周和第28-50周。在第二个治疗阶段（第28-50周），一些小鼠将继续接受与第一个治疗阶段相同的药物，而其他小鼠将接受不同的药物（以确定两种药物序贯治疗的疗效）或对照饲料（第4-28周）。仅在第一个治疗期接受药剂，然后接受对照饮食的小鼠将用于确定继续治疗的需要，而在第一个治疗期接受对照饮食，然后在第二个治疗期接受化学预防剂的小鼠将用于确定晚期干预预防癌症进展的功效。将在第20、28、38和48周通过MRI监测一些对照小鼠和贝沙罗汀治疗小鼠，以识别具有不同生长速率的肿瘤。总之，我们的预期结果是确定：i）使用同时和顺序治疗的由贝沙罗汀、SAHA、舒林酸组成的组合的化学预防功效，和ii）通过三种药剂及其组合调节mRNA表达。公共卫生相关性：有必要证明化学预防剂，包括药物组合，将预防肺癌的发展。联合使用化学预防剂，即，同时和顺序给药，将进行评估，以确定哪一种在预防肺癌方面具有更大的功效。将研究化学预防剂和药物组合对基因mRNA表达的调节，这可用于加速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