Abstract A102: Chemopreventive Efficacy and Mechanistic Studies of Targretin in the B[a]P-induced Mouse Lung Tumor Prevention Model

Abstract Aspiration route has been demonstrated to be as effective as inhalation in administering agents to lung with associated reduction in cost for equipment and chemopreventive agent. The current study evaluated the chemopreventive efficacy and mechanism (s) of Targretin, a novel oral synthetic retinoid that selectively binds and activates retinoid X receptors, via oropharyngeal aspiration against the strain A/J mouse lung adenoma induced by benzo[a]pyrene (B[a]P). Lung adenomas were induced in 8-week old female strain A/J mice by three oral gavages of B[a]P (2 mg /0.2 ml cotton seed oil). The mice were allowed 4 weeks to develop dysplasia, then given one of three doses of Targretin (0.1, 0.3 and 1 mg/kg) for 16 weeks. At different time points, the expression of a series of biomarkers (e.g., Cox-2 and 5-Lox at 2 and 16 weeks, survivin, PCNA and apoptosis at 16 weeks) in lung was evaluated by Western Blot and immunohistochemistry. Tumor incidence and multiplicity in the lung were measured following 16-week aspiration of Targretin and compared with B[a] P only group. Targretin showed dose-related inhibition of B[a]P-induced tumor incidence (p<0.05) at 0.1 and 0.3 mg/kg following 16-week treatment with no effect on tumor multiplicity. Targretin also showed dose-dependent inhibition of 5-Lox (25-47%) at 2 and 16 weeks, and Cox-2 (27-38%) and survivin (39-48%) at 16 weeks. A dose-dependent induction of apoptosis (2.2-3.0-fold) and a marginal but dose-dependent inhibition of PCNA were also observed at 16 weeks. In conclusion, this study demonstrated that Targretin via aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression. Also, it indicated that the aspiration route can be an excellent inexpensive alternative to inhalation for direct drug delivery to the rodent lung for efficacy testing of potential chemopreventive agents (Supported by NCI #N01-CN-53301). Citation Information: Cancer Prev Res 2010;3(12 Suppl):A102.