V. Edavana, Suzanne P Williams, David Caldwell
May 1, 2009
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Journal
Cancer Research
Abstract
Fulvestrant (Faslodex\#8482;) is used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Fulvestrant is a pure antiestrogen that has been shown to directly down-regulate the expression of the estrogen receptor. In in vivo and in vitro breast cancer models, fulvestrant has anticancer activity equivalent to tamoxifen and is superior to tamoxifen in some models. Previous studies have demonstrated that fulvestrant metabolism in human, involves multiple drug metabolizing enzyme families, including the cytochromes P450 and UDP-glucuronosyltransferases. To date, however, fulvestrant sulfation has not been characterized. We examined sulfation of fulvestrant using recombinant sulfotransferase (SULT) isoforms (SULT1A1, 1A3, 1B1, 1C1, 1C2, 1E1, 2A1, 2B1a and 2B1b). Of these isoforms, SULT1A1, which is the most widely expressed SULT, displayed the highest sulfating activity. We next examined expression of SULTs in laser capture microdissected breast tumors using qRT-PCR and found that SULT1A1, along with SULT2B1b, were the most highly expressed SULTs in breast tumors. SULT1A1 is also highly expressed in human liver; therefore we assayed fulvestrant sulfation in human liver cytosols from 100 individuals. There was wide interindividual variability in fulvestrant-sulfation capacity. Fulvestrant sulfation was significantly correlated with \#946;-naphthol sulfation (r=0.76, p Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5455.