R-FLURBIPROFEN CHEMOPREVENTION AND TREATMENT OF INTESTINAL ADENOMAS IN THE APC(MIN)- IMPLICATIONS FOR PROPHYLAXIS AND TREATMENT OF COLON-CANCER( MOUSE MODEL )

We used the C57BL/6J-APC(Min)/+ mouse (Min mouse) to evaluate the chem opreventive effects of R-flurbiprofen (R-FB), the noncyclooxygenase-in hibiting enantiomer of FB. Weanling Min mice were administered 6 weeks of oral treatment with R-FB using 2.5-25 mg/kg of R-FB once per day ( q.d.), 2.5-10 mg/kg of R-FB twice per day (b.i.d.), and 5 mg/kg of R-F B b.i.d. challenged with a high saturated fat diet, At necropsy we det ermined tumor and ulcer numbers, tumor size, and plasma levels of R- a nd S-FB. A linear dose response was observed from 2.5 to 10 mg/kg of R -FB, regardless of whether the drug was administered as a single or di vided dose. Reductions in tumor number were significant (P less than o r equal to 0.02) for doses of R-FB from 2.5 to 25 mg/kg/day. A dose of 5 mg/kg R-FB b.i.d. was able to overcome the doubling in tumor number associated with the high saturated fat diet, At 20 and 25 mg/kg/day R -FB, we obtained the maximum response with up to 90% inhibition of tot al tumor number, At these doses, however, there was toxicity and anima l deaths, This toxicity was associated with ulceration presumably resu lting from the in vivo epimerization of R- to S-FB that occurs in the mouse, Thus, we evaluated the oral pharmacokinetics of R-FB and its co nversion to S-FB in wild-type mice, These kinetics experiments reveale d inversion rates of 7.3 and 11.0% fur the 2.5 and 10 mg/kg R-FB doses , respectively, S-FB administered alone (0.5 and 2.0 mg/kg q.d.), in d oses mimicking the concentrations of S-FB associated with the R to S e pimerization of the doses of R-FB used in our experiments, had little or no antitumor efficacy (P > 0.05). Thus, we conclude that R-FB itsel f, nut the S-FB resulting from epimerization in the mouse, inhibits ad enoma formation in the Min mouse, In humans, where there is no R to S epimerization, it is possible that larger doses of R-FB can be used wi thout causing cyclooxygenase inhibition and its resulting ulcerogenici ty and other side effects, To assess the effect of R-FB on established adenomas, we allowed 40 Min mice to remain untreated until 70 days of age (the time of necropsy in the previous experiments) and then treat ed them for an additional 42 days with 10 mg/kg R-FB q.d. or 5 mg/kg R -FB b.i.d.. Both drug-treated groups demonstrated tumor numbers signif icantly less than that of the vehicle control (P < 0.01), Our results suggest that prophylaxis and treatment trials of R-FB should be extend ed to humans.