Estrogen Dependency of Uterine Leiomyoma

子宫肌瘤的雌激素依赖性

• 批准号: 7274676
• 负责人: Ayman Al-Hendy
• 金额: $ 3.74万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-24 至 2007-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274676
• 关键词: Adenoviruses; Adverse effects; Age; Agonist; Animal Model; Apoptosis; Apoptotic; Attenuated; Biological Assay; Biological Markers; Breast; Bromodeoxyuridine; Cardiovascular Diseases; Cell Cycle; Cell Line; Cell Proliferation; Cell physiology; Cells; Chemicals; Condition; Cyclin D1; Data; Dependence; Dependency; Development; Disease regression; Distant; Dominant-Negative Mutation; Elements; Endometrial Carcinoma; Endometrium; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Estrogens; Female; Female Genital Neoplasms; Fibroid Tumor; Genes; Goals; Hormones; Human; Hysterectomy; Image; Immune; Immune response; In Situ Nick-End Labeling; In Vitro; Incidence; Infertility; Injection of therapeutic agent; Intervention; Knowledge; Laboratories; Lead; Leiomyoma; Liver; Luciferases; Magnetic Resonance Imaging; Mammary gland; Measures; Menopause; Menorrhagia; Modeling; Molecular; Mus; Mutate; Nude Mice; Operative Surgical Procedures; Optruma; Organ; Osteoporosis; PECAM1 gene; Pelvic Pain; Pharmaceutical Preparations; Phenotype; Pregnancy; Premenopause; Proliferating; Proliferative Index; Raloxifene; Randomized; Rattus; Receptor Signaling; Safety; Sampling; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Tumor; Tamoxifen; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Angiogenesis; United States; Uterine Fibroids; Uterine Neoplasms; Vascular Endothelial Growth Factors; Virus; Week; Woman; Women' s Health; adenovirus mediated delivery; angiogenesis; calbindin; gene therapy; improved; in vivo; indexing; myometrium; pre-clinical; preclinical study; promoter; recombinant adenovirus treatment; reproductive; research study; response; size; steroid hormone; subcutaneous; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Uterine leiomyoma arise from the uterine smooth muscle compartment (myometrium) and are the most common gynecologic tumor in premenopausal women, occurring in up to 77% of all women. They are all significant cause of pelvic pain, menorrhagia, infertility, and pregnancy-related complications. These estrogen-dependent tumors are the leading indication for hysterectomy in reproductive age women. Currently, no medicinal therapy exists. Prolonged use of GnRH agonists, which can shrink tumors but induce a chemical menopause, is restricted due to serious side effects. The hormone-dependent phenotype of uterine leiomyoma suggests that interventions targeting the estrogen receptor (ER)-signaling pathway may have therapeutic efficacy. Proof-of-principal experiments have now established that treatment with anti-estrogen medications (e.g., tamoxifen and raloxifene) can significantly reduce tumor incidence, size, and proliferative index in the Eker rat, the only animal model known to acquire spontaneous uterine leiomyoma. Adenovirus-mediated delivery of a mutated dominant-negative ER (Ad-ER-DN) inhibited cell proliferation and induced apoptosis in human and rat leiomyoma cell lines. In a pilot experiment, Ad-ER-DN injected directly intratumor in nude mice with pre- existing fibroids induced immediate arrest and regression of tumor growth due to extensive apoptosis. explants in nude In this project, we will (Specific Aim 1) determine if Ad-ER-DN transduction inhibits endogenous ER signaling in estrogen-responsive rat and human leiomyoma cells, (Specific Aim 2) expand pilot results and evaluate the ability of Ad-ER-DN to ablate pre-established subcutaneous leiomyoma mice, and (Specific lira 3) conduct a pre-clinical trial to assess the ability of Ad-ER-DN to ablate uterine leiomyoma when delivered by direct intratumor injection in the immune-competent Eker rat. Tumor response will be correlated to proliferative and apoptotic indices, to markers of tumor angiogenesis, and to several estrogen-regulated genes. We will examine immune response and the safety of single vs. repeated recombinant adenovirus treatment alone or in combination with SERM (Raloxifene). Evident therapeutic potential aside, this project will add to our understanding of the molecular mechanisms of estrogen-dependence in this common uterine tumor. It will also show, in a well-characterized natural rat model, the effects of specific perturbing of ER signaling on several cellular functions (i.e., angiogenesis, apoptosis, and cell cycle). This knowledge will impact many other estrogen-related conditions (e.g., breast and endometrial cancer, cardiovascular disease, osteoporosis).

描述（由申请人提供）：子宫平滑肌瘤来自子宫平滑肌室（肌层），是绝经前妇女中最常见的妇科肿瘤，最多发生在所有女性中77％。它们都是导致骨盆疼痛，月经，不育和与妊娠有关的并发症的重要原因。这些依赖雌激素的肿瘤是生殖年龄女性子宫切除术的主要指示。目前，不存在药物疗法。长时间使用GnRH激动剂，可以缩小肿瘤但诱导化学更年期，这受到严重的副作用的限制。子宫平滑肌瘤的激素依赖性表型表明，针对雌激素受体（ER）信号途径的干预措施可能具有治疗功效。主要的主要实验已经确定，抗雌激素药物（例如，他莫昔芬和雷昔芬）的治疗可以显着降低Eker大鼠中唯一已知的自发性子宫静脉穿着肌瘤的唯一已知动物模型中的Eker大鼠的肿瘤发病率，大小和增殖指数。腺病毒介导的突变的显性阴性ER（AD-ER-DN）的递送抑制了人和大鼠平滑肌瘤细胞系中的细胞增殖和诱导的凋亡。在一个试点实验中，AD-DN在裸鼠中直接注射了肿瘤内的肿瘤内肌瘤，诱导了由于广泛的细胞凋亡而引起的肿瘤生长的立即停滞和消退。在该项目中的裸露植物中，我们将（特定目的1）确定AD-DN转导抑制雌激素反应性大鼠和人神经瘤细胞中的内源性ER信号传导（特定目的2）扩大了试验结果，并评估AD-ER-DN对消融能力的能力，以评估易于体现的Pree preatibal Subiciatos protibal contim contical contim contical procipanios contical scontication contical contical contical contical contical contical contical contical contical contication 3）通过直接肿瘤内注射在免疫能力的Eker大鼠中，Ad-er-dn浸泡子宫平滑肌瘤。肿瘤反应将与增殖和凋亡指数，肿瘤血管生成的标记以及几种雌激素调节的基因相关。我们将单独检查免疫反应和单一与重组腺病毒的重组治疗的安全性，或与SERM（raloxifene）结合使用。除了明显的治疗潜力外，该项目将增加我们对这种常见子宫肿瘤中雌激素依赖性的分子机制的理解。它还将在特征良好的自然大鼠模型中显示，ER信号转导的特定扰动对几种细胞功能（即血管生成，凋亡和细胞周期）的影响。这些知识将影响许多其他与雌激素相关的疾病（例如乳腺癌和子宫内膜癌，心血管疾病，骨质疏松症）。