Compound’s Dual Action Inhibited Oral Cancer

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Newswise — ANAHEIM, Calif. — The compound licofelone inhibited oral cancer growth by inhibiting the cyclooxygenase and 5-lipoxygenase pathways, with no observable side effects, according to data from a rat study presented at the 11th Annual AACR International Conference on Frontiers in Cancer Prevention Research, held here Oct. 16-19, 2012.

Cyclooxygenase (COX) inhibitors have been shown to suppress oral and other cancers, but side effects, such as gastric bleeding, tend to disqualify them as preventive agents. Researchers hypothesized that suppressing COX might instigate cancer-causing inflammation through lipoxygenase (LOX). Because licofelone inhibits both pathways, researchers investigated whether it could provide superior cancer prevention while lowering toxicity.

“Toxicology is always a limitation because you’re giving these preventive treatments to otherwise healthy people, so the threshold for toxicity is very low,” said lead researcher David McCormick, Ph.D., senior vice president and director at the ITT Research Institute in Chicago. “Dual inhibitors may provide superior chemopreventive activity, as well as a better toxicologic profile.”

Using a well-studied rat model, McCormick and colleagues induced oral cancer and tested different licofelone doses, including 37.5 mg/kg per day and 75 mg/kg per day, as well as 75 mg/kg per day after a six-week delay following the induction of cancer.

In a control group, 75 percent of rats developed squamous cell carcinoma, the predominant oral cancer in humans, most often at the base of the tongue. They also developed a variety of precancerous lesions.

Forty-three percent of rats assigned to high-dose licofelone and 55 percent assigned to the low-dose administration developed cancer. Those assigned to the compound after a six-week delay had a 34 percent incidence of oral cancer. McCormick noted that delayed administration can compromise the anticancer activity in some compounds. The fact that licofelone retained its anticancer action bodes well for its preventive potential, as patients may have already developed precancerous lesions before they seek treatment.

Researchers also observed a decreased incidence of the most advanced (highly invasive) cancers with licofelone: a 17 percent incidence with both doses compared with 54 percent in controls.

Although cancer incidence was reduced in the treated rats, the incidence of precursor lesions increased, again confirming licofelone’s ability to suppress the development of oral cancer, according to the researchers.

“The data suggest the compound inhibits cancer progression,” McCormick said. “The lower incidence of invasive cancer and higher incidence of cancer precursors indicate we may be stabilizing progression at the earlier, precancerous stage.”

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Abstract:

B110 Chemoprevention of rat oral carcinogenesis by licofelone, a dual cyclooxygenase/lipoxygenase inhibitor. David L. McCormick(1), Thomas L. Horn(1), William D. Johnson(1), Ronald A. Lubet(2), Vernon E. Steele(2). (1)IIT Research Institute, Chicago, IL, (2)National Cancer Institute, Bethesda, MD.

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]