TY - JOUR
T1 - Sulindac and sulindac metabolites in nipple aspirate fluid and effect on drug targets in a phase I Trial
AU - Thompson, Patricia A.
AU - Hsu, Chiu Hsieh
AU - Green, Sylvan
AU - Stopeck, Alison T.
AU - Johnson, Karen
AU - Alberts, David S.
AU - Chow, H. H.Sherry
PY - 2010/1
Y1 - 2010/1
N2 - 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 150mgtwice daily for 6weeks), 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 A2, a stable derivative of prostaglandin E2, 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.
AB - 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 150mgtwice daily for 6weeks), 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 A2, a stable derivative of prostaglandin E2, 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.
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U2 - 10.1158/1940-6207.CAPR-09-0120
DO - 10.1158/1940-6207.CAPR-09-0120
M3 - Article
C2 - 20051377
AN - SCOPUS:77649202008
SN - 1940-6207
VL - 3
SP - 101
EP - 107
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 1
ER -