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