title: Sulindac and sulindac metabolites in nipple aspirate fluid and effect on drug targets in a phase I trial.
abstract: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced risk of breast cancer. Sulindac, a nonselective NSAID with both cyclooxygenase-2-dependent and -independent activities, is a candidate for breast chemoprevention. We conducted a phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg daily and 150 mg twice daily for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A(2), a stable derivative of prostaglandin E(2), in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 in NAF in women receiving 150 mg twice daily (P = 0.038). These results are the first to show partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose-dependent effect of sulindac on growth differentiation factor 15 levels in NAF.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, 85724-5024, USA. pthompson@azcc.arizona.edu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Chiu-Hsieh
authors.initials: CH
authors.lastname: Hsu
authors.forename: Sylvan
authors.initials: S
authors.lastname: Green
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: Karen
authors.initials: K
authors.lastname: Johnson
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: H-H Sherry
authors.initials: HH
authors.lastname: Chow
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002097:C-Reactive Protein / Q000032:analysis / Q000187:drug effects; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055436:Growth Differentiation Factor 15 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D055966:Nipple Aspirate Fluid / Q000737:chemistry / Q000378:metabolism*; D013467:Sulindac / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D013467:Sulindac; C025087:15-keto-13,14-dihydroprostaglandin E2; D002097:C-Reactive Protein; D015232:Dinoprostone