Disease relevance of Droloxifene

• MATERIALS AND METHODS: Circulating NRP levels were determined in 94 patients who participated in a randomized trial of three different doses of the antiestrogen, droloxifene (DRO), as first-line HT for metastatic breast cancer [1].
• However, tamoxifen has been shown to increase the risk of endometrial cancer which has stimulated research for new effective antiestrogens, such as droloxifene and toremifene [2].
• The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy [3].
• PURPOSE: This trial was designed to demonstrate equivalence between droloxifene 40 mg/d and tamoxifen 20 mg/d as first-line treatment in pre- and post-menopausal women with ER+ and/or PgR+ advanced breast cancer based on time to disease progression and tumor response [4].
• Therefore, it can be assumed that Droloxifene may represent an important step forward in the treatment of mammary carcinomas in women through its better tolerability and increased efficacy compared with Tamoxifen [5].

High impact information on Droloxifene

• This effect was attenuated by pretreating cells for 15 minutes with 50 to 5000 ng/mL of 2-hydroxyestradiol (strong antioxidant but weak estrogen-receptor ligand) or 4-hydroxytamoxifen (strong antioxidant and potent estrogen-receptor ligand), but not by estrone or droloxifene (both weak antioxidants but potent estrogen-receptor ligands) [6].
• Only three of 32 patients (9%) with elevated NRP levels responded to DRO, compared with 35 of 62 (56%) with nonelevated NRP levels (P = .00001) [1].
• However, droloxifene also resulted in an 11.6% increase in vascular cell adhesion molecule-1 (P < 0.007) [7].
• Ten women were treated for 6 weeks with conjugated estrogen (Premarin), 0.625 mg/day, and droloxifene, 60 mg/day, in a double-blind crossover study with an intervening 4-week no-treatment period [8].
• Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women [9].

Chemical compound and disease context of Droloxifene

• Furthermore, droloxifene acts as a full estrogen antagonist on breast tissue and is being evaluated for treatment of advanced breast cancer [10].
• However, treatment with droloxifene or toremifene significantly reduced nitric oxide production by both MCF-7 and ZR-75-1 human breast cancer cell lines [11].
• The effect of droloxifene (3-hydroxytamoxifen) given as first-line endocrine treatment was evaluated in 39 postmenopausal women with advanced receptor-positive or receptor-unknown breast cancer [12].
• Steroid hormone levels in patients with advanced breast cancer during therapy with droloxifene: a pilot study [13].

Biological context of Droloxifene

• Raloxifene, tamoxifen, 4-hydroxytamoxifen, and droloxifene also fully blocked estrogen-mediated luciferase induction with IC50 values of 58.4, 89.2, 33.2, and 49.8 nM, respectively [14].
• These results suggested that droloxifene could induce apoptosis of luteal cells of rat in vitro [15].
• OBJECTIVE: The aim of this study was to evaluate the effect of conjugated equine oestrogen (CEE), and droloxifene, a selective oestrogen receptor modulator (SERM) on individual components of renin-angiotensin-aldosterone (RAAS) and blood pressure (BP) in postmenopausal women [16].
• Binding sites of droloxifene in the cytosol of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor cells [17].
• Effects of conjugated oestrogen and droloxifene on the renin-angiotensin system, blood pressure and renal blood flow in postmenopausal women [16].

Anatomical context of Droloxifene

• Cultured luteal cells of rats were incubated with droloxifene at various concentrations and with treatment durations [15].
• In this report, our goal was to identify estrogen regulated genes in the uterus and to compare the regulation by estrogen and tamoxifen with that of droloxifene [18].
• This inhibition of lipid peroxidation by droloxifene may result from a membrane stabilization that could be associated in cancer cells with decreased plasma membrane fluidity [19].
• Droloxifene was found to exhibit a membrane antioxidant ability in that it inhibited Fe(III)-ascorbate dependent lipid peroxidation in rat liver microsomes and ox-brain phospholipid liposomes [19].
• In vitro efficacy of known P-glycoprotein modulators compared to droloxifene E and Z: studies on a human T-cell leukemia cell line and their resistant variants [20].

Associations of Droloxifene with other chemical compounds

• The mean (+/- SD) serum TBG concentrations increased significantly during both treatment periods (baseline, 1.5+/-0.4 mg/dL; conjugated estrogens, 2.7+/-0.6 mg/dL; droloxifene, 2.1+/-0.6 mg/dL; P < 0.001 and P = 0.001, respectively) [8].
• The incidences of chromosomal structural abnormalities excluding gaps were: tamoxifen 4.3%, toremifene 0.8%, droloxifene 0.5%, diethylstilbestrol 0.8%, control 0.5% [21].
• With MCL-5 cells there was an increase in micronuclei with 4-hydroxytamoxifen, 4-hydroxytoremifene and clomifene but not with droloxifene [21].
• MCL-5 or Ho1 cells were incubated with 4-hydroxytamoxifen, 4-hydroxytoremifene, clomifene or droloxifene and the incidence of micronuclei estimated [21].
• Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339 [22].

Gene context of Droloxifene

• In patients in group 1, plasma lGF-I levels decreased by a mean value of 20% (P < 0.05) on treatment with droloxifene, while IGFBP-1 increased by a mean value of 45% (P > 0.1) [23].
• Droloxifene increased SHBG and suppressed FSH at all dosages and suppressed LH at the 40 and 100 mg dosages [24].
• Effects of droloxifene on apoptosis and Bax, Bcl-2 protein expression of luteal cells in pseudopregnant rats [25].
• However, no obvious differences in the intensity or localization could be found during various days of the pseudopregnancy, while an increase in Bax and a decrease in Bcl-2 protein expression could be induced by droloxifene treatment [25].
• We have confirmed this finding and also shown that the new anti-estrogen droloxifene inhibits the proliferation of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I)-stimulated MCF-7 cells [26].

Analytical, diagnostic and therapeutic context of Droloxifene

• Determination of droloxifene and two metabolites in serum by high-pressure liquid chromatography [27].
• Conjugated droloxifene could be estimated in a second run after treatment of sample with an enzyme preparation containing beta-glucuronidase plus sulphatase [27].
• A simple and highly sensitive reversed-phase fluorimetric HPLC method for the quantitation of droloxifene from rat, monkey, and human plasma as well as human serum is described [28].
• 2. Intraperitoneal injection of droloxifene (1 mg/kg) yielded an AUC0-omega approximately twice that observed following intraportal infusion or oral delivery of equal doses [29].

References