Fulvestrant (ICI 182,780)

Fulvestrant (ICI 182,780)は、選択的エストロゲン受容体(ER)拮抗薬である。エストロゲン受容体に結合し、ブロックし、分解し、その後、9.4 nMのIC₅₀でエストロゲン受容体(ER)を介した転写活性を阻害する^[1-3]。

Fulvestrant(3μM ;1ヶ月)は、H1975　NSCLC細胞のゲフィチニブに対する感受性を高める^[4]。Fulvestrant(1-10 μM;72 h)は、MDR細胞株においてドキソルビシン誘導性細胞毒性を強く感作した^[5]。

Fulvestrant(5 mg/マウス、皮下、週2回)は、マウス癌モデルでマクロファージと好中球の浸潤を有意に阻害した。Fulvestrantは、ヌードマウスのヒト乳がんにおけるエストラジオールの生理学的レベルの存在下でER+乳がんの成長を減少させる^[6]。Fulvestrant(5mg/マウス、週2回、皮下分離)とタモキシフェンの併用は腫瘍退縮を促進した^[7]。

References:

[1]. Vergote I, Robertson JF. Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials. Br J Cancer. 2004 Mar;90 Suppl 1(Suppl 1):S11-4. doi: 10.1038/sj.bjc.6601631. PMID: 15094759; PMCID: PMC2750769.

[2]. Osborne CK, Wakeling A, et,al. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer. 2004 Mar;90 Suppl 1(Suppl 1):S2-6. doi: 10.1038/sj.bjc.6601629. PMID: 15094757; PMCID: PMC2750773.

[3]. Dowsett M, Nicholson RI, et,al. Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat. 2005;93 Suppl 1:S11-8. doi: 10.1007/s10549-005-9037-3. PMID: 16247595.

[4]. Shen H, Liu J, et,al. Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression. Biomed Pharmacother. 2014 Apr;68(3):307-13. doi: 10.1016/j.biopha.2013.10.007. Epub 2013 Nov 7. PMID: 24268810.

[5]. Huang Y, Jiang D, et,al. Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression. Oncol Rep. 2017 Feb;37(2):705-712. doi: 10.3892/or.2016.5315. Epub 2016 Dec 14. PMID: 28000875; PMCID: PMC5355712.

[6]. Abrahamsson A, Rodriguez GV, et,al. Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen. Cancer Res. 2020 Oct 15;80(20):4487-4499. doi: 10.1158/0008-5472.CAN-20-1705. Epub 2020 Aug 27. PMID: 32855207.
[7]. Mishra AK, Abrahamsson A, et,al. Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERα positive breast cancer by up-regulation of ERβ. Oncotarget. 2016 Aug 30;7(35):56876-56888. doi: 10.18632/oncotarget.10871. PMID: 27486755; PMCID: PMC5302959.