Browsing by Subject "aromatase"

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    Aromatase inhibitors produce hypersensitivity in experimental models of pain : studies in vivo and in isolated sensory neurons
    (2014) Robarge, Jason Dennis; Flockhart, David A.; Fehrenbacher, Jill C.; Khanna, Rajesh; Skaar, Todd C.; Vasko, Michael R.
    Aromatase inhibitors (AIs) are the current standard of care for the treatment of hormone receptor positive breast cancer in postmenopausal women. Nearly one-half of patients receiving AI therapy develop musculoskeletal toxicity that is characterized by joint and/or muscle pain and approximately one-fourth of patients discontinue their therapy as a result of musculoskeletal pain. Since there are no effective strategies for prevention or treatment, insight into the mechanisms of AI-induced pain is critical to improve treatment. However, there are few studies of AI effects in animal models of nociception. To determine whether AIs produce hypersensitivity in animal models of pain, I examined the effects of AI administration on mechanical, thermal, and chemical sensitivity in rats. The results demonstrate that (1) repeated injection of 5 mg/kg letrozole in male rats produces mechanical, but not thermal, hypersensitivity that extinguishes when drug dosing is stopped; (2) administering a single dose of 1 or 5 mg/kg letrozole in ovariectomized (OVX) rats also induces mechanical hypersensitivity, without altering thermal sensitivity and (3) a single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats augments flinching behavior induced by intraplantar ATP injection. To determine whether the effects of AIs on nociceptive behaviors are mediated by activation or sensitization of peptidergic sensory neurons, I determined whether letrozole exposure alters release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons and from sensory nerve endings in rat spinal cord slices. No changes in basal, capsaicin-evoked or high extracellular potassium-evoked CGRP release were observed in sensory neuronal cultures acutely or chronically exposed to letrozole. Furthermore, letrozole exposure did not alter the ability of ATP to augment CGRP release from sensory neurons in culture. Finally, chronic letrozole treatment did not augment neuropeptide release from spinal cord slices. Taken together, these results do not support altered release of this neuropeptide into the spinal cord as mediator of letrozole-induced mechanical hypersensitivity and suggest the involvement of other mechanisms. Results from this dissertation provide a new experimental model for AI-induced hypersensitivity that could be beneficial in delineating mechanisms mediating pain during AI therapy.
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    Men with acute cholecystitis have higher tissue-based cytokine levels than women: a cross-sectional study
    (2015-04) Fehrenbacher, Jill C.; Bingener, J.; Aho, J. M.; Wasky, P. R.; Locke, E. E.; Schwesinger, W. H.; Van Sickle, K. R.; Hargreaves, K. M.; Department of Pharmacology and Toxicology, IU School of Medicine
    Aim. Sex-based differences in surgical outcomes may be related to socioeconomic, behavioral, or physiologic factors. Estrogenreceptor-related modulation is a proposed mechanism for sex-based differences in reaction to inflammation. We evaluated sex-based differences in gallbladder tissue-levels of inflammatory cytokines using a novel method to collect interstitial fluid from cholecystectomy samples. Methods. Patients undergoing laparoscopic cholecystectomy for acute or chronic cholecystitis were prospectively enrolled from August 1, 2006, through August 1, 2009. Immediately after gallbladder removal, interstitial fluid from the gallbladder fundus and infundibulum was collected. Tissue-level cytokines were determined using a multiplex cytometric bead assay. Messenger RNA levels of estrogen receptors and aromatase (ESR1, GPER, CYP19A1) were analyzed with real-time reverse transcriptasepolymerase chain reaction. Results. Interstitial fluid from gallbladder tissue of 78 patients (48 women) was analyzed. All patients with acute cholecystitis had higher levels of interleukin (IL)-6 and IL-10 than patients with chronic cholecystitis. Men with acute disease had higher tissue levels of IL-6 and IL-8 than women. IL-1β and IL-10 were increased only in men with acute cholecystitis. Tumor necrosis factor-α levels did not vary by sex or disease status. Tissues from acutely inflamed gallbladders had higher expression of a G protein-coupled estrogen receptor (GPER) and aromatase (CYP19A1). Conclusion. Tissue-level proinflammatory cytokines differ between men and women with acute cholecystitis. Mechanistic studies are needed to determine whether changes in cytokine levels or estrogen function contribute to local tissue inflammation and whether these influence surgical outcomes.
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    Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors that Also Modulate Estrogen Receptors
    (ACS, 2016) Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A.; Cushman, Mark; Department of Medicine, IU School of Medicine
    A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.