Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma: Evaluation of potential chemopreventive activity

Clara N Curiel, Susan M. Swetter, Janine G Einspahr, Chiu-Hsieh Hsu, Raymond B Nagle, Paul Sagerman, Joseph Tangrea, Howard Parnes, David S Alberts, Hsiao-Hui Chow

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5848-5856
Number of pages9
JournalCancer
Volume118
Issue number23
DOIs
StatePublished - Dec 1 2012

Fingerprint

Sulindac
Nevus
Melanoma
Placebos
Vascular Endothelial Growth Factor A
Anti-Inflammatory Agents
Caspase 3
Biomarkers
Pharmaceutical Preparations
Melanocytes
Biological Availability

Keywords

  • anti-inflammatory agents
  • atypical nevi
  • chemoprevention
  • melanoma
  • nevus
  • nonsteroidal
  • prevention and control

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma : Evaluation of potential chemopreventive activity. / Curiel, Clara N; Swetter, Susan M.; Einspahr, Janine G; Hsu, Chiu-Hsieh; Nagle, Raymond B; Sagerman, Paul; Tangrea, Joseph; Parnes, Howard; Alberts, David S; Chow, Hsiao-Hui.

In: Cancer, Vol. 118, No. 23, 01.12.2012, p. 5848-5856.

Research output: Contribution to journalArticle

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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.",
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author = "Curiel, {Clara N} and Swetter, {Susan M.} and Einspahr, {Janine G} and Chiu-Hsieh Hsu and Nagle, {Raymond B} and Paul Sagerman and Joseph Tangrea and Howard Parnes and Alberts, {David S} and Hsiao-Hui Chow",
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T1 - Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma

T2 - Evaluation of potential chemopreventive activity

AU - Curiel, Clara N

AU - Swetter, Susan M.

AU - Einspahr, Janine G

AU - Hsu, Chiu-Hsieh

AU - Nagle, Raymond B

AU - Sagerman, Paul

AU - Tangrea, Joseph

AU - Parnes, Howard

AU - Alberts, David S

AU - Chow, Hsiao-Hui

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N2 - 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.

AB - 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.

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KW - chemoprevention

KW - melanoma

KW - nevus

KW - nonsteroidal

KW - prevention and control

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