Abstract
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.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAID), which exert their biologic action primarily through inhibition of COX enzymes, have been a major focus in the field of chemoprevention for more than 25 years
We examined the effects of naproxen, nitric oxide (NO)-naproxen, sulindac, NO-sulindac, and DFMO administered alone or together with one of the NSAIDs in the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancers in rats
Results with naproxen and NO-naproxen We had previously shown that higher doses of naproxen (400 ppm) and NO-naproxen (560 ppm) were effective in preventing the development of urinary bladder cancers in the OH-BBN model [13]
Summary
Nonsteroidal anti-inflammatory drugs (NSAID), which exert their biologic action primarily through inhibition of COX enzymes, have been a major focus in the field of chemoprevention for more than 25 years. The primary agents investigated were the standard nonselective. Authors' Affiliations: 1Cancer Prevention Fellowship Program, Nutritional Science Research Group; 2Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; Departments of 3Surgery and 4Genetics, University of Alabama at Birmingham, Birmingham, Alabama; 5Hormel Institute, Austin, Minnesota; 6Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and 7Eicosanoid Core Laboratory, Division of Clinical Pharmacology, Vanderbilt School of Medicine, Nashville, Tennessee. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). H.L. Nicastro and C.J. Grubbs contributed to this work.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.