Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (
NSAID)
naproxen (a standard
NSAID with a good cardiovascular profile),
sulindac, and their
nitric oxide (NO) derivatives. In addition, the effects of the
ornithine decarboxylase inhibitor,
difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of
naproxen or
sulindac was examined. Agents were evaluated at their human equivalent doses (HED), as well as at lower doses. In the hydroxybutyl(butyl)
nitrosamine (
OH-BBN) model of
urinary bladder cancer,
naproxen (400 or 75 ppm) and
sulindac (400 ppm) reduced the incidence of large
bladder cancers by 82%, 68%, and 44%, respectively, when the agents were initially given 3 months after the final dose of the
carcinogen; microscopic
cancers already existed.
NO-naproxen was highly effective, whereas NO-
sulindac was inactive. To further compare
naproxen and
NO-naproxen, we examined their effects on gene expression in rat livers following a 7-day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent
NSAID. When agents were initiated 2 weeks after the last administration of
OH-BBN, DFMO at 1,000 ppm had limited activity, a low dose of
naproxen (75 ppm) and
sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of
naproxen had minimal effects, whereas the combination of DMFO and
sulindac was more active than either agent alone. Thus,
naproxen and
NO-naproxen were highly effective, whereas
sulindac was moderately effective in the
OH-BBN model at their HEDs.