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.
RCT Entities:
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: Joanne M Jeter; Tawnya L Bowles; Clara Curiel-Lewandrowski; Susan M Swetter; Fabian V Filipp; Zalfa A Abdel-Malek; Larisa J Geskin; Jerry D Brewer; Jack L Arbiser; Jeffrey E Gershenwald; Emily Y Chu; John M Kirkwood; Neil F Box; Pauline Funchain; David E Fisher; Kari L Kendra; Ashfaq A Marghoob; Suephy C Chen; Michael E Ming; Mark R Albertini; John T Vetto; Kim A Margolin; Sherry L Pagoto; Jennifer L Hay; Douglas Grossman; Darrel L Ellis; Mohammed Kashani-Sabet; Aaron R Mangold; Svetomir N Markovic; Frank L Meyskens; Kelly C Nelson; Jennifer G Powers; June K Robinson; Debjani Sahni; Aleksandar Sekulic; Vernon K Sondak; Maria L Wei; Jonathan S Zager; Robert P Dellavalle; John A Thompson; Martin A Weinstock; Sancy A Leachman; Pamela B Cassidy Journal: Cancer Date: 2018-10-03 Impact factor: 6.860
Authors: Karen Colbert Maresso; Kenneth Y Tsai; Powel H Brown; Eva Szabo; Scott Lippman; Ernest T Hawk Journal: CA Cancer J Clin Date: 2015-08-18 Impact factor: 508.702
Authors: Elizabeth S Borden; Anngela C Adams; Kenneth H Buetow; Melissa A Wilson; Julie E Bauman; Clara Curiel-Lewandrowski; H-H Sherry Chow; Bonnie J LaFleur; Karen Taraszka Hastings Journal: Cancers (Basel) Date: 2021-12-21 Impact factor: 6.575