6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): A new irreversible aromatase inhibitor

Giudici, D.; Ornati, G.; Briatico, G.; Buzzetti, Franco; Lombardi, Paolo; Salle, E. Di

doi:10.1016/0022-4731(88)90129-x

Cited by 141 publications

(54 citation statements)

References 11 publications

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“…These include the following approaches: (a) antagonists of ER function through drugs, such as tamoxifen and raloxifene; (b) down-regulation of ER function through agents, such as those used in this particular study ( fulvestrant); and (c) reduction of estrogen levels through aromatase inhibitors, such as the reversible nonsteroidal agents letrozole and anastrozole (34) and the irreversible steroidal inactivator exemestane (35). Tamoxifen and raloxifene have partial agonistic effects in tissues, such as endometrium.…”

Section: Discussionmentioning

confidence: 99%

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

Stabile

Lyker²,

Gubish³

et al. 2005

Cancer Research

289

301

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Identifying new effective therapeutic treatments for lung cancer is critical to improving overall patient survival. We have targeted both the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) pathways using an ER antagonist, fulvestrant (''Faslodex''), and the selective EGFR tyrosine kinase inhibitor, gefitinib (''Iressa''), in nonsmall cell lung cancer (NSCLC) cells. Rapid activation of phospho-EGFR and phospho-p44/p42 mitogen-activated protein kinase by estrogen was observed, indicating nonnuclear ER transactivation of EGFR. Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells. Cell growth and apoptosis were examined in several NSCLC lines that express varying amounts of ERB, EGFR, and Neu but no full-length ERa. One cell line contained an EGFR mutation. Cells were exposed to 10 nmol/L estrogen and 10 ng/mL EGF and either 1 Mmol/L fulvestrant or 1 Mmol/L gefitinib alone or in combination. In all cell lines, the drug combination decreased cell proliferation up to 90% and increased apoptosis 2-fold. The relative responses to gefitinib and fulvestrant were similar regardless of ER and EGFR expression and mutation status. In an in vivo lung tumor xenograft model, the drug combination decreased tumor volume in severe combined immunodeficient mice by f60% compared with 49% and 32% for gefitinib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by biochemical and histologic evidence of increased apoptosis, decreased phospho-p44/p42 mitogen-activated protein kinase expression, and increased Ki-67 expression compared with individual treatment. These studies provide evidence of a functional interaction between the ER and the EGFR pathways in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

Stabile

Lyker²,

Gubish³

et al. 2005

Cancer Research

289

301

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“…Other thirdgeneration AIs developed during this period were the nonsteroidal agents vorozole (since discontinued) and anastrozole [73] (Fig. 2) [66] and the steroidal agent exemestane [74]. AIs have been classified as steroidal (type I; for example, exemestane) or nonsteroidal (type II; for example, letrozole and anastrozole) [75].…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

The discovery and mechanism of action of letrozole

Bhatnagar

2007

Breast Cancer Res Treat

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Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara 1 ) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

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“…4) and anastrozole (5,6). EXE is structurally related to androstenedione and has some affinity for the androgen receptor (3,7). The principal metabolite of EXE is 17-hydroexemestane (17-H-EXE), which has a short half-life but, like the parent compound, is androgenic (7).…”

Section: Introductionmentioning

confidence: 99%

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

Goss

Cheung

et al. 2004

Clinical Cancer Research

110

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Purpose: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats.Experimental Design: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined.Results: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls.Conclusions: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.

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6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): A new irreversible aromatase inhibitor

Cited by 141 publications

References 11 publications

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

The discovery and mechanism of action of letrozole

Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats

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