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There is a clear need to develop effective chemoprevention strategies to reduce the high incidence of lung cancer. The purpose of the this study was to evaluate the effectiveness of two targeted approaches, reversal of gene silencing by methylation through demethylation therapy and the induction of apoptosis through activation of the PPAR-γ pathway. A chemoprevention study was designed in which A/J mice that are highly susceptible to lung cancer were treated with the tobacco carcinogen, NNK. Animals were held for 42 wks to allow the development of pre-invasive lesions: alveolar hyperplasias and adenomas. At that time mice were separated into 12 groups of 15 mice and treated for 6 weeks with individual or a combination of the agents. The agents used were hydralazine (Hyd), selenium (Se), sodium phenylbutyrate (PheB), valproic acid (VPA), iloprost (Ilo), and rosiglitazone (Ros). Not all combinations could be evaluated due to number of treated mice. Following sacrifice, the number of lesions was determined for each animal by evaluating H&E stained sections that included all lung lobes. Lesions were classified as hyperplasia, adenoma, or carcinoma. The most dramatic effects on tumor progression were seen in the groups in which Ros was administered. The number of hyperplasias increased by 52%, while the number of adenomas was decreased by 31% (p < 0.05) with Ros treatment alone compared to sham. The combination of Ros, Se, Hyd, and PheB, but not when VPA was used instead of PheB, resulted in a further decrease in adenomas (38%). There were too few carcinomas to accurately assess treatment effects. The area and volume of hyperplasias and adenomas from sham and these two treatment groups were quantified. While Ros treatment alone did not significantly affect the size of either lesion, striking effects were seen in the combination therapy group. The volume of the hyperplasias and adenomas were decreased by 42% and 67%, respectively (p < 0.005). Similar effects were seen when examining area of the lesion. Morphometry evaluations are continuing to determine whether any other treatment affected the size of the lesions in the absence of effects on progression. Biomarkers for Ros and PheB activity (e.g., PPAR-γ expression) and lesion growth (e.g., Ki67) are being evaluated. These studies provide compelling evidence that Ros treatment alone and in combination with PheB can dramatically affect lung tumor development by blocking the progression of hyperplasias to adenomas and through affecting the clonal expansion of these lesions. These exciting findings could ultimately lead to a new prevention strategy in the war against lung cancer. (Supported by CA095568 and a fellowship from IASLC).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA