Abstract 2869: Chemopreventive efficacy and mechanism of licofelone in mouse lung tumor model

Abstract

Abstract Our previous study comparing inhalation and aspiration methods of administration of an agent to lung airway epithelia indicated that aspiration can be an equally effective route of exposure while reducing the need for inhalation equipment and amount of chemopreventive agent required. The current study evaluated the chemopreventive efficacy and mechanism of Licofelone, a dual inhibitor of cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-Lox), against the strain A/J mouse lung adenoma induced by benzo[a]pyrene (B[a]P). The Licofelone was administered to the lung via oropharyngeal aspiration. Lung adenomas were induced in 8-wk 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 left for 4 weeks to develop dysplasia, then given one of three doses of Licofelone (0.03, 0.1 and 0.3 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 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 Licofelone and compared with B[a] P only group. The data showed that Licofelone inhibited Cox-2 (26-42%) and 5-Lox (43-61%) in a dose-dependent manner at 2 weeks. Both survivin (16-25%) and PCNA (41-61%) were also inhibited in a dose-dependent manner. There was a 2.4 fold induction of apoptosis at 0.3 mg/kg when compared to the B[a] P only group. Licofelone showed significant dose-related inhibition of B[a]P-induced tumor incidence (p = <0.05) and multiplicity at 0.03 and 0.1 mg/kg following 16-week treatment. In conclusion, this study demonstrated that Licofelone administered by aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression. Also, it showed that the aspiration route can be an excellent alternative to inhalation for direct delivery of drugs to the rodent lung. (Supported by NCI #N01-CN-53301). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2869.