15-keto-13-14-dihydroprostaglandin-e2 and Breast-Neoplasms

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.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Carcinoma, Ductal, Breast; Chromatography, High Pressure Liquid; Dinoprostone; Female; Genetic Predisposition to Disease; Growth Differentiation Factor 15; Humans; Nipple Aspirate Fluid; Sulindac; Tissue Distribution

We describe a time-resolved fluoroimmunoassay method for the determination of 13,14-dihydro-15-ketoprostaglandin E2 (PGEM) and 13,14-dihydro-15-ketoprostaglandin F2 alpha (PGFM) in femtomolar ranges. Polyclonal antibodies were raised in rabbits and the antigen was labelled with europium by the avidin-biotin technique. A second antibody, directed to rabbit IgG, was coated onto the solid phase. The IgG-PG-europium complex was bound by the second antibody, giving a rapid and complete separation of antibody-bound and free antigen. The detection limit was 0.2 pg/assay for PGFM and 1.2 pg/assay for PGEM. The intra-assay CV ranged from 4.6% to 9.3% and the interassay CV from 6.7% to 11.4%. A good correlation was obtained between the results from TR-FIA and RIA when the method was applied to the investigation of tissues from breast cancer. We conclude that the TR-FIA is more sensitive and much faster than the RIA and avoids the use of radioactive material.

Topics: Bacterial Proteins; Binding, Competitive; Biotin; Breast Neoplasms; Dinoprost; Dinoprostone; Europium; Fluoroimmunoassay; Humans; Prostaglandins; Radioimmunoassay; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Streptavidin