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    Development of a New Animal Model and Treatment Strategies for Aromatase Inhibitor-Associated Arthralgia

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    Author
    Yang, Gee Su
    0000-0002-9098-719X
    Advisor
    Renn, Cynthia L.
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    Background: Aromatase inhibitors (AIs) are widely used as the most effective adjuvant chemotherapy for postmenopausal women with breast cancer. Unfortunately, nearly half of women receiving AIs have reported AI-associated arthralgia (AIA), which may increase cancer-related mortality and non-adherence to the therapy. As of now, no clear biological mechanisms of AIA have been found partially due to a lack of relevant animal models, and consequently, few beneficial treatments have been developed for AIA. Purpose: The purpose of this dissertation is to establish a clinically relevant animal model of AIA, and to examine potential treatment strategies for attenuating AIA by focusing on anti-nociceptive properties of curcumin (turmeric) and physical exercise. Methods: To mimic the clinical condition of AIA, female immune-deficient mice underwent tumor transplantation on flanks, surgical removal of grown tumors (~300 mm3) and ovaries, and subcutaneous injections of letrozole (10µg/day for 8 weeks). Mice weekly received behavior assays of musculoskeletal pain and physical function at pre-tumor baseline, post-tumor removal, and during AI treatment. To test effects of curcumin or physical exercise on AIA, letrozole-treated mice were given either 45 mg/kg curcumin or peanut oil (vehicle) orally, or they were housed either in cages with free voluntary running wheels or cages with locked wheels for five weeks, respectively. Following the interventions, protein expression levels of brain-derived neurotrophic factor (BDNF), a critical molecular moderator of pain behavior, were evaluated in the spinal dorsal horn. Results: Eight weeks of letrozole injections significantly induced mechanical allodynia, thermal (cold) allodynia, joint hypersensitivity, decreased grip strength, worsened motor coordination, and anteroposterior weight shift. Curcumin administration improved almost all deteriorated nocifensive behavior and neuromuscular function except for mechanical allodynia. Physical exercise enhanced the deteriorated nocifensive behavior but did not rescue neuromuscular dysfunction. BDNF protein expression levels were down-regulated following curcumin administration and physical exercise. Conclusion: This animal model is clinically relevant to AIA with face validity. It will provide an important platform to better understand progression and characteristics of AIA and allow examination of factors that cause AIA symptoms. Curcumin and physical exercise could be considered as effective interventions to reduce AIA symptoms and warrant studies in humans.
    Description
    University of Maryland, Baltimore. Nursing. Ph.D. 2017
    Keyword
    Breast--Cancer
    Aromatase Inhibitors--adverse effects
    Arthralgia
    Curcumin
    Exercise
    Models, Animal
    Musculoskeletal Pain
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/6726
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    Theses and Dissertations School of Nursing
    Theses and Dissertations All Schools

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