title: Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma: evaluation of potential chemopreventive activity.
abstract: BACKGROUND
  Reduced melanoma risk has been reported with regular use of nonsteroidal anti-inflammatory drugs (NSAIDs). However, the ability of NSAIDs to reach melanocytes in vivo and modulate key biomarkers in preneoplastic lesions such as atypical nevi has not been evaluated.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled trial of sulindac was conducted in individuals with atypical nevi (AN) to determine bioavailability of sulindac and metabolites in nevi and effect on apoptosis and vascular endothelial growth factor A (VEGFA) expression in AN. Fifty subjects with AN ≥ 4 mm in size and 1 benign nevus (BN) were randomized to sulindac (150 mg twice a day) or placebo for 8 weeks. Two AN were randomized for baseline excision, and 2 AN and BN were excised after intervention.
  
  
  RESULTS
  Postintervention sulindac, sulindac sulfone, and sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, and 2.25 ± 2.24 μg/mL in plasma, and 0.51 ± 1.05, 1.38 ± 2.86, and 0.12 ± 0.12 μg/g in BN, respectively. Sulindac intervention did not significantly change VEGFA expression but did increase expression of the apoptotic marker cleaved caspase-3 in AN (increase of 3 ± 33 in sulindac vs decrease of 25 ± 45 in the placebo arm, P = .0056), although significance was attenuated (P = .1103) after adjusting for baseline expression.
  
  
  CONCLUSIONS
  Eight weeks of sulindac intervention resulted in high concentrations of sulindac sulfone, a proapoptotic metabolite, in BN but did not effectively modulate VEGFA and cleaved caspase-3 expression. Study limitations included limited exposure time to sulindac and the need to optimize a panel of biomarkers for NSAID intervention studies.
authors.affiliation: College of Medicine, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024, USA. ccuriel@azcc.arizona.edu
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.forename: Susan M
authors.initials: SM
authors.lastname: Swetter
authors.forename: Janine G
authors.initials: JG
authors.lastname: Einspahr
authors.forename: Chiu-Hsieh
authors.initials: CH
authors.lastname: Hsu
authors.forename: Ray
authors.initials: R
authors.lastname: Nagle
authors.forename: Paul
authors.initials: P
authors.lastname: Sagerman
authors.forename: Joseph
authors.initials: J
authors.lastname: Tangrea
authors.forename: Howard
authors.initials: H
authors.lastname: Parnes
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Chow
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008545:Melanoma / Q000517:prevention & control*; D008875:Middle Aged; D009506:Nevus / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000517:prevention & control*; D013467:Sulindac / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D042461:Vascular Endothelial Growth Factor A; D013467:Sulindac; D053148:Caspase 3