Fulvestrant (ICI-182780, ZD 9238, ZM 182780) is anestrogen receptor (ER)antagonist withIC50of 0.94 nM in a cell-free assay. Fulvestrant also inducesautophagyandapoptosisand has antitumor activity. In vitro
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.
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. Cell Data
