Chemoprevention of intestinal adenomas in the Apc(Min) mouse by piroxicam:kinetics, strain effects and resistance to chemosuppression

Previous cancer chemoprevention studies have demonstrated that NSAIDs can b e effective in suppressing the development of intestinal tumors. To further explore this issue, we performed cross-over chemoprevention studies using the drug piroxicam in the Apc(Min) mouse to evaluate the kinetics of NSAID- mediated tumor regression, the effects of genetic background and the incide nce of resistance to chemoprevention, Starting at the time of weaning, C57B l/6J-Apc(Min) mice were fed either the control diet (AIN-93G) or AIN-93G pl us 200 p.p.m. piroxicam, Tumor multiplicity was significantly reduced in Ap c(Min) mice that were fed 200 p.p.m. piroxicam until 100 or 200 days of age (94.4 and 95.7% reduction in tumor number, respectively; P < 0.001 versus AIN-93G controls). When the administration of piroxicam was delayed until 1 00 days of age and the mice were killed at 200 days of age, tumor multiplic ity was reduced by 96.2% (P < 0.001 versus controls), Alternatively, when t he administration of piroxicam was suspended at 100 days of age and the mic e were killed at 200 days of age, tumor multiplicity was reduced by 68.0% ( P < 0.001 versus controls). Short-term drug treatment periods for Apc(Min) animals with established tumors revealed that the kinetics of piroxicam-ind uced tumor regression were rapid: >90% reduction in tumor multiplicity was observed after 1 week of treatment with 200 p.p.m. piroxicam. The distribut ion of residual tumors in piroxicam-treated mice suggests that tumors of th e duodenum and colon were relatively resistant to chemosuppression, Treatme nt of interspecific hybrid Apc(Min) mice with 200 p.p.m. piroxicam revealed that there was a strain-related effect on chemosuppression, suggesting the existence of genetic elements which modulate NSAID chemosensitivity, Final ly, whole-genome allelic loss studies showed that there were few unique chr omosomal deletions in the NSAID-resistant tumors from F1 mice, implying tha t loss-of-function mutations secondary to Ape inactivation are not likely t o account for the observed difference in chemoresistance.