ICI 182,780 (Faslodex?)

Abstract

BACKGROUND The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (Faslodex™) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models. METHODS ICI 182,780 was tested in a large number of in vitro and in vivo preclinical models, and its value was assessed clinically when administered before surgery for breast carcinoma and hysterectomy for benign conditions and after failure of tamoxifen in patients with advanced breast carcinoma. RESULTS All data indicated that ICI 182,780 is devoid of agonist activity in preclinical models and in clinical trials. It inhibits growth of the breast and endometrium. In animal models, it does not cross the blood‐brain barrier and appears to be neutral with respect to lipids and bone. ICI 182,780 down‐regulates the estrogen receptor and is active in tamoxifen‐resistant breast carcinoma. In a small, Phase II study, durable responses were seen: Phase III clinical trials are in progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment of patients with advanced breast carcinoma. CONCLUSIONS ICI 182,780 specifically down‐regulates the estrogen receptor and, thus, represents the first of a new class of therapeutic agents. In this report, the authors present the current evidence that distinguishes ICI 182,780 from tamoxifen and related nonsteroidal compounds and establishes ICI 182,780 as the first in a new class of therapeutic agents. Cancer 2000;89:817–25. © 2000 American Cancer Society.

Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance

“…In our in vivo model of tamoxifen resistance we also found that AZD8931 in combination with tamoxifen significantly slowed growth. Fulvestrant alone also significantly slowed tamoxifen- resistant tumor growth in vivo as has been previously shown [42]. This suggests that in tamoxifen-resistant breast cancer cells, ER still plays a role in promoting growth, As previously shown, increased HER signaling can either modify ER activity to promote endocrine resistance [5, 29], or can promote additional alternative signaling to bypass ER [43].…”

Dioscin promotes osteoblastic proliferation and differentiation via Lrp5 and ER pathway in mouse and human osteoblast-like cell lines

“…ICI 182,780 (Faslodex) from AstraZeneca (Cheshire, United Kingdom) is considered as a pure steroidal estrogen antagonist that was designed to be devoid of estrogen agonist action in both in vivo and in vitro models [41,42]. It can abolish estrogen agonist activity by competing with endogenous estrogen for ERs presented in the nuclei of estrogen responsive tissues [41,42]. As Figure  6B, E and Figure  6B, F shown, the expressions of ER-α (P < 0.05) and ER-β (P < 0.01) were blocked by ICI 182,780.…”

Tamoxifen Resistance: Emerging Molecular Targets

“…Following this, the TAM-ER dimer binds to DNA at palindromic ERE sequences in the promoter region of E2 responsive genes. Transcription of the E2 responsive gene(s) is attenuated because the AF2, ligand-dependent domain is inactive, and ER co-activator binding is reduced by the TAM-ER complex; partial agonist activity results from the AF1 domain, which remains active in the TAM-ER complex [51] (Figure 2). …”