Abstract B110: Chemoprevention of rat oral carcinogenesis by licofelone, a dual cyclooxygenase/lipoxygenase inhibitor

Cyclooxygenase [COX] inhibitors [piroxicam, celecoxib, naproxen, and NO-naproxen] are potent inhibitors of oral carcinogenesis induced in rats by 4-nitroquinoline-1-oxide [NQO]. By contrast, a model 5-lipoxygenase [LOX] inhibitor [zileuton] has no chemopreventive activity in the rat NQO oral cancer model. Bifunctional agents such as licofelone [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid] can inhibit both COX and LOX pathways of eicosanoid biosynthesis. As a result of these activities, dual COX/LOX inhibitors (a) may be less toxic than inhibitors of a single pathway of arachidonic acid metabolism, and (b) may prevent redirection of eicosanoid biosynthesis into parallel pathways that stimulate inflammation and carcinogenesis. A chemoprevention efficacy evaluation of dual COX/LOX inhibition was performed using licofelone as a model compound. Squamous cell carcinomas of the tongue were induced in male F344 rats by administration of NQO [20 ppm] in the drinking water for 10 weeks. Beginning two days after completion of NQO administration, groups of 30 rats received daily oral [gavage] administration of licofelone at 0 mg/kg/day [vehicle control], 37.5 mg/kg/day [low dose], or 75 mg/kg/day [high dose]. A fourth experimental group received oral [gavage] administration of 75 mg licofelone/kg beginning 6 weeks post-NQO [high dose, delayed intervention]. Licofelone or vehicle administration was continued until study termination at week 25. When administered beginning two days after NQO, licofelone conferred dose-related protection against oral carcinogenesis [55% and 43% incidences of oral cancer in low and high dose groups, respectively, versus 75% in controls; p < 0.05 for high dose group]. Delayed administration of the high dose of licofelone demonstrated the greatest chemopreventive activity [34% oral cancer incidence versus 75% incidence in controls; p < 0.01]. Licofelone may inhibit oral carcinogenesis by delaying cancer progression; rats receiving the high dose of licofelone starting either 2 days or 6 weeks post-NQO demonstrated (a) decreases in the incidence of the most invasive [+4] cancers [17% in both groups versus 54% in controls; p < 0.01] and (b) increases in the number of rats without invasive malignancies [normal epithelium or epithelial hyperplasia only; 37% and 41% incidence versus 11% in controls; p < 0.01 for both comparisons]. The chemopreventive activity of the low dose of licofelone was marginally significant [0.05 < p < 0.10 for both comparisons]. Licofelone also prevented the pre-terminal body weight loss commonly seen in animals with advanced oral cancer in this model. These data demonstrate that licofelone is an effective inhibitor of oral carcinogenesis induced in rats by NQO, and suggest that licofelone chemopreventive activity results from inhibition or delayed progression of preneoplastic lesions to invasive oral cancers. The chemopreventive activity of delayed administration of licofelone is particularly notable because clinical trials are most likely to involve individuals with preexisting oral lesions. Dual COX/LOX inhibitors may provide an approach to oral cancer prevention that is not limited by the toxicity induced by specific of inhibitors of either COX or LOX. [Supported by NCI-N01-CN-25113] Citation Format: David L. McCormick, Thomas L. Horn, William D. Johnson, Ronald A. Lubet, Vernon E. Steele. Chemoprevention of rat oral carcinogenesis by licofelone, a dual cyclooxygenase/ lipoxygenase inhibitor. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B110.