Abstract
Nonsteroidal anti‐inflammatory drugs (NSAIDs) 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 (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO‐naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity as well as the expectation that the production of NO itself might be therapeutically effective. When examined in the hydroxybutyl(butyl)nitrosamine (OH‐BBN) rat urinary bladder cancer model, naproxen at doses of either 400 or 200 ppm in the diet greatly decreased the development of large invasive bladder cancers when treatment was initiated shortly after the last OH‐BBN dosing. In a second study, naproxen at 133 ppm or NO‐naproxen at 183 or 550 ppm caused striking decreases in the incidence of large tumors. Surprisingly, if treatments were started three months after the last OH‐BBN (when multiple microscopic lesions already exist) both NO‐naproxen (550 ppm) and naproxen (400 ppm) were still highly effective (91–96% decreases); implying that most of their effects are late. In the azoxymethane (AOM)‐induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm reduced mean ACFs in the colon by approximatley 45–60%. NO‐naproxen administered at roughly equimolar doses (300 and 600 ppm), reduced total ACF by 20–40%, respectively. In contrast, in the methylnitrosourea (MNU)‐induced ER+ mammary cancer model in rats (where most NSAIDs are relatively ineffective) neither NO‐naproxen nor naproxen showed significant inhibition at doses of 550 and 400 ppm. These data show that both naproxen and NO‐naproxen are effective agents against urinary bladder and colon (but not mammary) carcinogenesis. Additional data showing the effects of sulindac and NO‐sulindac in the urinary bladder model will also be presented. Data also imply that both naproxen and NO‐naproxen are effective, but that the NO‐derivative does not appear to be more effective.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A94.
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