Lung cancer is the leading cause of cancer-related deaths with 5 year survival rates of <15% in humans. Thus, chemopreventive strategies are needed to prevent lung tumor progression before irreversible lesions develop. Our laboratory has developed a bitransgenic mouse lung tumor model that constitutively expresses the human Ki-rasG12C allele in a doxycycline (DOX)-inducible and lung-specific manner. This model appears to recapitulate the earliest stages of lung tumorigenesis as the lung lesions that developed were predominantly benign hyperplastic lesions and adenomas. We have initiated studies using this animal model to determine the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on lung tumor progression. One week after the initiation of DOX administration (500 μg/ml in the drinking water) to up-regulate mutant RAS transgene expression, mice were treated with 6 weekly i.p. injections of the lung tumor promoter butylated hydroxytoluene (BHT, 200 mg/kg). Results obtained from short term studies in which mice were euthanized 24 hr after the last BHT injection suggest that when given in the diet, Sulindac can inhibit lung tumor progression. Co-treatment with DOX and BHT increased tumor multiplicity to 4.2±1.3 (n=6) compared with treatment of DOX alone (2.5±0.5,n=5). All mice in both treatment groups developed adenomas. At dietary levels of 100 mg/kg, Sulindac decreased tumor multiplicity in the co-treated DOX/BHT mice to 2.0±1.4 (n=4), with one of the four mice exhibiting no tumor formation at all. Statistical analysis using ANOVA revealed that BHT caused a marginally significant increase in lung tumor multiplicity in DOX/BHT treated mice compared to mice treated with DOX alone (p=.073), which could be due to both the small number of mice/group as well as the early time point of tumor analysis. Sulindac, however, was associated with a significant (p=0.033) chemopreventive effect by decreasing tumor multiplicity in mice co-treated with BHT and DOX. Immunohistochemical analysis demonstrated increased COX-2 and iNOS expression in the focal hyperplastic lesions within the lung of the DOX/BHT treated mice. Mice treated with DOX alone had hyperplastic lung foci without associated COX-2 or iNOS expression while those treated with BHT alone, which had no tumor lesions, exhibited COX-2 and iNOS expression confined to alveolar macrophages. Neither COX-2 nor iNOS were expressed in Clara and alveolar type II cells in mice treated with Sulindac, DOX, and BHT. The data suggest that even at a very early time-point, Sulindac has an inhibitory effect on the promotional phase of lung carcinogenesis, resulting in decreased tumor multiplicity. These results suggest a possible chemopreventive role of NSAIDS in reducing the development of lung tumors in the at-risk population of smokers. Further ongoing long term studies should provide more definitive data on the role of various NSAIDS on the inhibition of lung tumor progression in this mouse model.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]