Prevention of hydroxybutyl(butyl)nitrosamine(OH-BBN)-induced urinary bladder cancer in Fischer-344 rats by cyclooxygenase and lipoxygenase inhibitors.

B83

The purpose of this research project was to determine the efficacy of the cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors, alone or in combination, to prevent OH-BBN-induced urinary bladder cancers in female Fischer-344 rats. In this OH-BBN-induced rat model, the bladder cancers are primarily transitional cell carcinomas which are mostly papillary and slowly growing. The rats were treated for 8 weeks with OH-BBN beginning at 49 days of age, then treated with chemopreventive agents and followed for an additional 6-7 months for the appearance of urinary bladder cancers. Beginning one week following the last OH-BBN administration and continuing until the end of the study, celecoxib (a COX2 inhibitor) was administered at 500 mg/kg diet, zileuton (a LOX inhibitor) at 1200 mg/kg diet, naproxen (a nonspecific COX inhibitor) at 200 or 400 mg/kg diet, aspirin (a COX1 inhibitor) at 300 and 3000 mg/kg diet, and caffeic acid (a LOX inhibitor) at 8 and 16 grams/kg diet. At the end of the study (months after final OH-BBN treatment) celecoxib showed a 76% decrease in bladder cancer weight, zileuton, a 43% decrease, and the combination, an 81% decrease, compared to controls. Naproxen at the high dose inhibited 70% and at the low dose 75% of cancers. Aspirin treatment resulted in a 33% and 44% inhibition at low and high doses, respectfully. Caffeic acid inhibited bladder cancers at the high dose only by 10%. Celecoxib and Naproxen demonstrated the most efficacy in these studies. While celecoxib and zileuton showed significant chemopreventive effect alone there was no additive or synergistic effect seen using the combination. Aspirin and caffeic acid, (COX and LOX inhibitors, respectively) were also modestly effective and noneffective respectively in inhibiting urinary bladder cancer. These results add strength to the hypothesis that arachidonic acid metabolism inhibitors are an effective class of agents against bladder cancer. Supported by NCI contract N01-CN25115.