Fulvestrant (ICI 182780; ZD 9238; ZM 182780) is a synthetic and potent estrogen receptor (ER) antagonist with IC50 of 0.94 nM in a cell-free assay. Unlike tamoxifen, which has partial agonist effects, and the aromatase inhibitors, which reduce the estrogen available to tumor cells, fulvestrant binds competitively to estrogen receptors in breast cancer cells, resulting in estrogen receptor deformation and decreased estrogen binding. In vitro studies indicate that fulvestrant reversibly inhibits the growth of tamoxifen-resistant, estrogen-sensitive, human breast cancer cell lines.
理化性质和储存条件
| Molecular Weight (MW) | 606.77 |
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| Formula | C32H47F5O3S |
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| CAS No. | 129453-61-8 |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 100 mg/mL (164.8 mM) |
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| Water: <1 mg/mL |
| Ethanol: 100 mg/mL (164.8 mM) |
| Solubility (In vivo) | 5% DMSO+95% Corn oil: 30mg/mL |
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| Synonyms | ZD9238; ZD-9238; ZD 9238; ICI 182780; ICI182780; ICI-182780; ZM182780; ZM 182780; ZM-182780; Fulvestrant; Faslodex. |
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实验参考方法
| In Vitro | In vitro activity: Fulvestrant is an effective inhibitor of the growth of ER-positive MCF-7 (with IC50 of 0.29 nM) but with no effect on the growth of ER-negative BT-20 human breast cancer cells. Fulvestrant causes accumulation of cells in G0/G1 and also reduces the proportion of cells capable of continued DNA synthesis. Fulvestrant competitively inhibits binding of oestradiol to the estrogen receptor. Fulvestrant blocks nuclear localization of the ER through impairing receptor dimerisation, and energy-dependent nucleo-cytoplasmic shuttling. Because of the instability of fulvestrant-ER complex, the binding of Fulvestrant with ER finally results in accelerated degradation of the ER protein. Fulvestrant (10 nM) not only decreases IGF-IR mRNA levels but also decreases the half-life. Treatment with 100 μM Fulvestrant leads to a time dependent increase of TNFR1 and TRADD steady-state mRNA levels in MCF-7 cells. Fulvestrant is capable of down-regulating androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells. Fulvestrant also significantly attenuates R1881-stimulated growth by 70%. Fulvestrant is able to modulate mitosis and cell death in immature cerebellar neurons via rapid activation of MAPK.
Cell Assay: MCF-7 cells are cultured in multiwell plates (24-well, seeding density 4 × 104) in minimal essential medium containing phenol red, insulin (10 μg/mL), and 5% charcoal-stripped fetal calf serum without additional estradiol. Fulvestrant and/or estradiol are added in fresh medium 2 days after seeding. Cultures are maintained for 5 days with one further medium change and growth is assessed by measurement of total cell protein at the beginning and end of treatment and compared with that of controls treated with ethanol (0.1%) alone. |
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| In Vivo | Fulvestrant is devoid of uterotropic activity, and when co-administered with estradiol, it effectively blocks the uterotropic action of estradiol with ED50 of 0.06 mg/kg/day s.c. in immature female rats. A single s.c. injection of 5 mg of Fulvestrant suspension blocks completely the growth of MCF-7 xenografts. The growth of transplants of the BrlO human breast tumor is also suppressed effectively by 10 μM Fulvestrant. Fulvestrant (10 mg/rat, s.c.) reduces the androgen receptor expression, ERK1/2 phosphorylation and cell proliferation in the rat ventral prostate. Fulvestrant also displays anti-angiogenesis in the chick egg chorioallantoic membrane. |
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| Animal model | The human breast cancer xenografts MCF-7 in nude mice |
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| Formulation & Dosage | Formulated to 50 mg/mL in arachis oil; 5 mg/mouse; s.c. injection |
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| References | Cancer Res. 1991 Aug 1;51(15):3867-73; J Neurosci. 2003 Jun 15;23(12):4984-95. |
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