Abstract
Fulvestrant (Faslodex™) is a pure antiestrogen that is effective in treating estrogen receptor-(ER) positive breast cancer tumors that are resistant to selective estrogen receptor modulators such as tamoxifen. Clinical trials investigating the utility of adding fulvestrant to other therapeutics have not been shown to affect cytochrome P450-mediated metabolism. Effects on phase II metabolism and drug resistance have not been explored. This study demonstrates that fulvestrant up regulates the expression of UDP glucuronosyltransferase 1A4 (UGT1A4) >2.5- and >3.5-fold in MCF7 and HepG2 cells, respectively. Up regulation occurred in a time- and concentration-dependent manner, and was inhibited by siRNA silencing of ERα. Fulvestrant also up regulates multidrug resistance-associated proteins (MRPs). There was an up regulation of MRP2 (1.5- and 3.5-fold), and MRP3 (5.5- and 4.5-fold) in MCF7 and HepG2 cell lines, respectively, and an up regulation of MRP1 (4-fold) in MCF7 cells. UGT1A4 mRNA up regulation was significantly correlated with UGT1A4 protein expression, anastrozole glucuronidation, ERα mRNA expression and MRP mRNA expression, but not with ERα protein expression. Genetic variants in the UGT1A4 promoter (-163A, -217G and -219T) reduced the basal activity of UGT1A4 by 40-60%. In silico analysis indicated that transcription factor c-Myb binding capacity may be affected by these variations. Luciferase activity assays demonstrate that silencing c-Myb abolished UGT1A4 up regulation by fulvestrant in promoters with the common genotype (-163G, -217 T and -219C) in MCF7 cells. These data indicate that fulvestrant can influence the disposition of other UGT1A4 substrates. These findings suggest a clinically significant role for UGT1A4 and MRPs in drug efficacy.
Highlights
Fulvestrant (FaslodexTM; ICI 182,780) belongs to a novel class of endocrine agents for the treatment of breast cancer (Howell et al 2000; Osborne et al 2004)
UDP glucuronosyltransferase 1A4 (UGT1A4) was up regulated by fulvestrant treatment, and the expression of UGT1A4 essentially plateaus at concentrations higher than 10 nM (Figure 1a)
After treatment with 10 nM fulvestrant, cells were harvested at different time points (0, 24, 48, 72 and 96 hrs) and mRNA levels were determined by qRT-PCR
Summary
Fulvestrant (FaslodexTM; ICI 182,780) belongs to a novel class of endocrine agents for the treatment of breast cancer (Howell et al 2000; Osborne et al 2004). Fulvestrant shows no estrogen agonist activity, and has been regarded as an important improvement in breast cancer therapy It is thought that co-administration of fulvestrant with other therapeutics may be beneficial, and clinical trials investigating this are being conducted (Group 2004; AstraZeneca 2012). The effect of co-administration on phase II drug metabolism and drug disposition has not yet been reported. Altered rates of metabolism can affect systemic availability and elimination half-life of xenobiotics. This can affect toxicity or therapeutic effect, and may result in undesirable drug-drug interactions. A better understanding of simultaneous regulation of metabolism and disposition may help prevent these undesirable effects
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