Growth Inhibition Induced by Mifepristone in Ovarian Cancer

米非司酮引起的卵巢癌生长抑制

• 批准号: 7497487
• 负责人: Carlos Marcelo Telleria
• 金额: $ 13.87万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-18 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497487
• 关键词: Adverse effects; Affinity; Agonist; Animals; Antineoplastic Agents; Binding; Breast Cancer Cell; Cancer Cell Growth; Cancer Patient; Cancer cell line; Caring; Cause of Death; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell membrane; Cells; Chronic Disease; Cisplatin; Clinic; Clinical Research; Combined Modality Therapy; Cyclin-Dependent Kinase Inhibitor; Cytostatics; Cytotoxic Chemotherapy; Cytotoxic agent; DNA Synthesis Inhibition; Data; Development; Diagnosis; Disease; Dissection; Dose; Early Diagnosis; Effectiveness; Endocrine; Epigenetic Process; Epithelial; Epithelial ovarian cancer; Epithelium; Evaluation; Event; Experimental Models; Failure; Feasibility Studies; Female Genital Diseases; Gene Expression; Genetic; Genetic Transcription; Glucocorticoid Receptor; Goals; Growth; Growth Inhibitors; Health; Hormonal; Human; Immunocompromised Host; Immunoprecipitation; In Vitro; Injection of therapeutic agent; Investigation; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Messenger RNA; Mifepristone; Molecular; Molecular Target; Multiple Pregnancy; Mus; Mutation; Nuclear Receptors; Nude Mice; Operative Surgical Procedures; Ovarian; Patients; Pharmaceutical Preparations; Phase; Phase Transition; Physiologic pulse; Physiological; Platinum; Premalignant; Prevention; Progesterone; Progesterone Receptors; Progestins; Protein Isoforms; Pulse taking; RU-486; Recurrence; Relative (related person); Reporter Genes; Research Personnel; Research Proposals; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Staging; Standards of Weights and Measures; Steroids; Surface; Synthetic Progestogens; Testing; Therapeutic; Therapeutic Agents; Time; Up-Regulation; Western Blotting; Woman; Work; Xenograft procedure; base; cancer cell; carcinogenesis; cell growth; chemotherapeutic agent; chemotherapy; cytotoxic; cytotoxicity; design; hormone therapy; human CDK2 protein; immunosuppressed; improved; in vitro Model; in vivo; insight; killings; neoplastic; novel strategies; novel therapeutics; outcome forecast; pre-clinical; prevent; progesterone receptor B; programs; receptor; research study; success; synergism; tumor; tumor growth

DESCRIPTION (provided by applicant): The overall goal of this application is to study the feasibility of using the prototypical progesterone receptor modulator mifepristone, also known as "RU486," for ovarian cancer therapeutics. Ovarian cancer is the leading cause of death in women from gynecologic diseases, in part because of the difficulty in performing early diagnosis, and also due to the lack of successful treatment strategies. Treatment for ovarian cancer generally involves cytoreductive surgery followed by platinum-based chemotherapy, yet the major barrier that this treatment encounters is the development of chemoresistance, which leads to therapeutic failure. It is therefore clear that new therapeutic options for patients with advanced disease are desperately needed. Our preliminary data have demonstrated that mifepristone not only is a cytostatic agent for ovarian cancer cells, but also enhances the cytotoxicity of the standard chemotherapeutic agent cisplatin. These results led to the hypothesis that mifepristone can be exploited therapeutically in two manners: first as a cytostatic agent blocking the repopulation of cells that had survived chemotherapy; and second, enhancing chemotherapy-induced lethality. Specific aim 1 will identify the underlying molecular mechanism of the cytostatic effect of mifepristone in cultured ovarian cancer cells, and will test the efficacy of the compound in an in vivo setting using immunocompromised mice. Specific aim 2, using ovarian cancer cell lines of similar genetic backgrounds but carrying different sensitivities to cisplatin, will define whether mifepristone prevents repopulation of cancer cells in between rounds of cisplatin chemotherapy and the mechanism whereby it enhances cisplatin-mediated lethality. Results from this investigation have the potential for a major impact on human health because combination of mifepristone with standard cytotoxic chemotherapy would allow a reduction in the effective dose of cytotoxic drugs leading to reduced toxic side effects, lower chemoresistance and longer survival. At present there is no hormonal therapy approved for the treatment of any type of ovarian malignancy, yet the rationale of our preliminary results suggest that mifepristone is a promising hormonal therapeutic agent to be added to the list of anti-epithelial ovarian cancer drugs with the final goal of converting this lethal cancer into a treatable chronic disease.

描述（由申请人提供）：本申请的总体目标是研究使用原型孕酮受体调节剂米非司酮（也称为“RU486”）用于卵巢癌治疗的可行性。卵巢癌是女性妇科疾病死亡的主要原因，部分原因是难以进行早期诊断，也由于缺乏成功的治疗策略。卵巢癌的治疗通常涉及细胞减灭手术，然后进行铂类化疗，但这种治疗遇到的主要障碍是化疗耐药性的产生，从而导致治疗失败。因此，很明显，晚期疾病患者迫切需要新的治疗选择。我们的初步数据表明，米非司酮不仅是卵巢癌细胞的细胞抑制剂，而且还能增强标准化疗药物顺铂的细胞毒性。这些结果导致了这样的假设：米非司酮可以通过两种方式进行治疗：首先作为细胞抑制剂，阻止化疗后存活的细胞重新增殖；其次，增强化疗引起的致死率。具体目标 1 将确定米非司酮在培养的卵巢癌细胞中细胞抑制作用的潜在分子机制，并使用免疫功能低下的小鼠在体内环境中测试该化合物的功效。具体目标2，使用具有相似遗传背景但对顺铂具有不同敏感性的卵巢癌细胞系，将确定米非司酮是否可以在顺铂化疗轮次之间阻止癌细胞的增殖，以及它增强顺铂介导的致死率的机制。这项研究的结果有可能对人类健康产生重大影响，因为米非司酮与标准细胞毒性化疗的结合可以减少细胞毒性药物的有效剂量，从而减少毒副作用、降低化疗耐药性并延长生存期。目前，尚无激素疗法被批准用于治疗任何类型的卵巢恶性肿瘤，但我们初步结果的基本原理表明，米非司酮是一种有前途的激素治疗剂，将被添加到抗上皮性卵巢癌药物列表中，最终目标是将这种致命的癌症转化为可治疗的慢性疾病。