Nonsteroidal anti-inflammatory drugs (NSAID) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically, and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal ulceration and may increase cardiovascular events. Naproxen seems to cause the lowest cardiovascular events of the common NSAIDs other than aspirin. Nitric oxide (NO)-naproxen was tested based on the finding that adding a NO group to NSAIDs may help alleviate GI toxicity. In the azoxymethane-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45% to 60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm) and reduced total ACF by 20% to 40%, respectively. In the hydroxybutyl (butyl) nitrosamine rat urinary bladder cancer model, NO-naproxen was given at 183 or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, whereas the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started 3 months after hydroxybutyl (butyl) nitrosamine, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86-94% decreases). In the methylnitrosourea-induced mammary cancer model in rats, NO-naproxen and naproxen showed nonsignificant inhibitions (12% and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis.Perhaps the most strikingly positive group of agents tested to prevent colon, urinary bladder, and skin cancers in experimental animal models are the various specific and nonspecific cyclooxygenase (COX) inhibitors. It was shown over 20 years ago that nonspecific nonsteroidal anti-inflammatory drugs (NSAID) were highly effective in the azoxymethane (AOM)-induced rat colon cancer model and the hydroxybutyl (butyl) nitrosamine (OH-BBN)-induced rodent urinary bladder cancer model. Several years ago, our laboratories found that celecoxib, which preferentially inhibits COX-2 activity, was similarly effective in these models (1, 2). These latter findings helped validate COX-2 as a potential target for chemoprevention in a number of organs, including skin cancer (3-5). The studies also helped to support clinical trials in the prevention of colon adenomas and skin cancer (6).Although the clinical chemoprevention results with celecoxib in the colon and skin seem promising, they must be balanced against the increase in cardiovascular (CV) problems associated with the selective COX-2 inhibitors (7). Although these CV problems are clearly associated with rofecoxib at its standard dose, major problems associated with the standard dose of celecoxib are less clear, although higher doses do yield an increase in CV events. Naproxen, which seems to have fewer CV effects than most NSAI...
