Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma

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 mu g/mL in plasma, and 0.51 +/- 1.05, 1.38 +/- 2.86, and 0.12 +/- 0.12 mu g/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. Cancer 2012. (c) 2012 American Cancer Society.