title: The chemopreventive efficacies of nonsteroidal anti-inflammatory drugs: the relationship of short-term biomarkers to long-term skin tumor outcome.
abstract: The ultraviolet B (UVB) component of sunlight, which causes DNA damage and inflammation, is the major cause of nonmelanoma skin cancer (NMSC), the most prevalent of all cancers. Nonsteroidal anti-inflammatory drugs (NSAID) and coxibs have been shown to be effective chemoprevention agents in multiple preclinical trials, including NMSC, colon, and urinary bladder cancer. NSAIDs, however, cause gastrointestinal irritation, which led to the recent development of nitric oxide (NO) derivatives that may partially ameliorate this toxicity. This study compared the efficacy of several NSAIDs and NO-NSAIDs on UV-induced NMSC in SKH-1 hairless mice and determined whether various short-term biomarkers were predictive of long-term tumor outcome with these agents. Naproxen at 100 (P = 0.05) and 400 ppm (P < 0.01) in the diet reduced tumor multiplicity by 26% and 63%, respectively. The NO-naproxen at slightly lower molar doses shows similar activities. Aspirin at 60 or 750 ppm in the diet reduced tumor multiplicity by 19% and 50%, whereas the equivalent doses (108 and 1,350 ppm) were slightly less effective. Sulindac at 25 and 150 ppm in the diet, doses far below the human equivalent dose was the most potent NSAID with reductions of 50% and 94%, respectively. In testing short-term biomarkers, we found that agents that reduce UV-induced prostaglandin E2 synthesis and/or inhibit UV-induced keratinocyte proliferation yielded long-term tumor efficacy.
authors.affiliation: The Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Mikulec
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Rundhaug
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Simper
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001241:Aspirin / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D009288:Naproxen / Q000494:pharmacology; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013467:Sulindac / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014408:Biomarkers, Tumor; D013467:Sulindac; D009288:Naproxen; D015232:Dinoprostone; D001241:Aspirin