Browsing by Subject "Letrozole"

Now showing 1 - 6 of 6
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    Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor α
    (American Association of Cancer Research, 2020-06-15) Ingle, James N.; Cairns, Junmei; Suman, Vera J.; Shepherd, Lois E.; Fasching, Peter A.; Hoskin, Tanya L.; Singh, Ravinder J.; Desta, Zeruesenay; Kalari, Krishna R.; Ellis, Matthew J.; Goss, Paul E.; Chen, Bingshu E.; Volz, Bernhard; Barman, Poulami; Carlson, Erin E.; Haddad, Tufia; Goetz, Matthew P.; Goodnature, Barbara; Cuellar, Matthew E.; Walters, Michael A.; Correia, Cristina; Kaufmann, Scott H.; Weinshilboum, Richard M.; Wang, Liewei; Medicine, School of Medicine
    Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental design: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. Conclusions: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.
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    Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons
    (Elsevier, 2016-07) Robarge, Jason D.; Duarte, Djane B.; Shariat, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.; Pharmacology and Toxicology, School of Medicine
    Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats.
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    Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer
    (Springer, 2017-02) Robarge, Jason D.; Desta, Zereunesay; Nguyen, Anne T.; Li, Lang; Hertz, Daniel; Rae, James M.; Hayes, Daniel F.; Storniolo, Anna M.; Stearns, Vered; Flockhart, David A.; Skaar, Todd C.; Henry, N. Lynn; Medicine, School of Medicine
    PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were
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    Letrozole targets the human ether-a-go-go-related gene potassium current in glioblastoma
    (Wiley, 2021) Shugg, Tyler; Dave, Nimita; Amarh, Enoch; Assiri, Abdullah A.; Pollok, Karen E.; Overholser, Brian R.; Medicine, School of Medicine
    Aberrant expression of human ether-a-go-go-related gene (hERG) potassium channels has been implicated in the pathophysiology of glioblastoma (GBM). Letrozole has demonstrated efficacy in pre-clinical GBM models. The objective of this research was to assess the potential for hERG inhibition by letrozole to mediate efficacy in GBM. hERG currents were assessed using patch clamp electrophysiology in an overexpression system during treatment with letrozole, exemestane, or vehicle (dimethyl sulfoxide). Relative to vehicle, peak hERG tail current density was reduced when treated with 300 nM and 1 μM letrozole but not when treated with exemestane (up to 1 μM). Cell proliferation was assessed in cultured glioblastoma cell lines (U87 and U373) treated with letrozole, exemestane, doxazosin (hERG blocker), or vehicle. Letrozole, but not exemestane, reduced cell proliferation relative to vehicle in U87 and U373 cells. The associations between expression of hERG (KCNH2), aromatase (CYP19A1), and the estrogen receptors (ESR1 and ESR2) and time to all-cause mortality were assessed in GBM patients within The Cancer Genome Atlas (TCGA) database. hERG expression was associated with reduced overall survival in the TCGA GBM cohort. Future work is warranted to investigate hERG expression as a potential biomarker to predict the therapeutic potential of hERG inhibitors in GBM.
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    Treatment of Girls and Boys with McCune-Albright Syndrome with Precocious Puberty - Update 2017
    (Y S Medical Media Ltd, 2017-12) Neyman, Anna; Eugster, Erica A.; Pediatrics, School of Medicine
    The most common endocrinopathy associated with McCune-Albright Syndrome (MAS) is peripheral precocious puberty (PP) which occurs far more often in girls than in boys. We will discuss the latest advancements in the treatment of precocious puberty in MAS that have been achieved during the past 10 years. However, due to the rarity of the condition and the heterogeneity of the disease, research in this field is limited particularly in regards to treatment in boys. In girls, a period of watchful waiting is recommended prior to initiating therapy due to extreme variability in the clinical course. This article will review in detail current pharmacologic treatment in girls, which typically consists of either inhibiting estrogen production or blocking estrogen action at the level of the end-organ. The two treatments with the most evidence at this time are Tamoxifen (which is an estrogen receptor modulator) and Letrozole (which is a 3rd generation aromatase inhibitor). This article will also review the current treatment strategies in boys which typically include using an androgen receptor blocker and an aromatase inhibitor. Due to the rarity of the condition, large multicenter collaborative studies are needed to further investigate efficacy and safety with the goal of establishing the gold standard for treatment of PP in children with MAS.
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    Variable Aromatase Inhibitor Plasma Concentrations Do Not Correlate with Circulating Estrogen Concentrations in Post-Menopausal Breast Cancer Patients
    (SpringerLink, 2017-10) Hertz, Daniel L.; Speth, Kelly A.; Kidwell, Kelley M.; Gersch, Christina L.; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.; Medicine, School of Medicine
    Purpose: The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Results: Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Conclusions: Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.