Characterization and prevention of chemotherapy-induced damage to ovarian reserve

化疗引起的卵巢储备功能损害的特征和预防

• 批准号: 7494152
• 负责人: KUTLUK H OKTAY
• 金额: $ 29.8万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494152
• 关键词: ATM Signaling Pathway; Adjuvant; Adjuvant Chemotherapy; Adjuvant Therapy; Age; Albumins; Antineoplastic Agents; Antral; Apoptosis; Apoptotic; Binding; Biochemical Markers; Biological Preservation; Blood Tests; Blood Vessels; Breast Cancer Treatment; Cancer Patient; Cell Death; Cells; Ceramides; Cessation of life; Chemotherapy-Oncologic Procedure; Cleaved cell; Clinical Research; Clinical Trials; Combination Chemotherapy; Complication; Counseling; Count; Cyclophosphamide/Paclitaxel; DNA Repair Gene; Data; Docetaxel/Doxorubicin; Dyes; Effectiveness; Endocrine; Estradiol; Failure; Fertility; Follicle Stimulating Hormone; Future; Goals; Hormones; Human; Imagery; Immunodeficient Mouse; Individual; Infertility; Injection of therapeutic agent; Injury; Late Effects; Malignant Neoplasms; Measurement; Measures; Menstruation; Methods; Modeling; Molecular; Mus; Oocytes; Operative Surgical Procedures; Ovarian; Ovarian Tissue; Ovarian hormone; Ovary; Paclitaxel; Patients; Pattern; Periodicity; Population; Prevention; Primates; Primordial Follicle; Proteins; Public Health; Quality of life; Radiation therapy; Relative (related person); Research Personnel; Risk; Rodent; SCID Mice; Serum; Sphingosine; Staging; Survival Rate; Testing; Time; Toxic effect; Toxicity due to chemotherapy; Treatment Protocols; Trees; Ultrasonography; Woman; Xenograft Model; Xenograft procedure; base; cancer therapy; caspase-3; chemotherapeutic agent; chemotherapy; cost; density; follow-up; improved; inhibin B; inhibitor/antagonist; malignant breast neoplasm; mullerian-inhibiting hormone; prevent; protective effect; receptor; repaired; reproductive; research study; treatment planning

DESCRIPTION (provided by applicant): Chemotherapy-induced ovarian failure is a growing public health problem with a major impact on quality of life. If individual toxicity of chemotherapy agents is known, patients can be counseled about the likelihood of ovarian damage and the need for fertility preservation. Moreover, if pharmacological ovarian protection strategies are developed, there will be no need for surgical interventions to preserve fertility, thus reducing concomitant risks and costs. The long term goal of this project is to improve our understanding of the risks of chemotherapy-induced ovarian failure by developing more accurate ovarian reserve assessment strategies and xenografting models, in addition to testing the effectiveness of pharmacological approaches to prevent chemotherapy induced damage to ovarian reserve in a xenograft model. The proposal focuses on breast cancer since it is the most common malignancy in young women. The specific aims are: (1) To determine the impact of commonly used breast cancer chemotherapy regimens on ovarian reserve using existing and emerging markers of the follicle population. Antral follicle counts, Inhibin-B, anti-mullerian hormone, and FSH/estradiol measurements will be obtained pre-and post-chemotherapy with a 2.0-4.5 year follow-up. (2) To measure the degree and determine the mechanism of damage caused by chemotherapeutics in human ovary. Immunodeficient mice with human ovarian tissue xenografts will be treated with commonly used and emerging agents, or the vehicle; changes in follicle density, as well as the extent of apoptotic follicular death as quantified by pre-cleaved caspase-3 expression will be used to measure the impact. An alternative mechanism of follicular loss by microvascular damage will also be investigated by quantitative vascular assessment methods and intra-vital dye injection. Moreover, we will investigate whether double strand DMA breaks are induced in the surviving primordial follicles by the analysis of ATM pathway proteins involved in DMA repair. (3) To determine whether a cell death inhibitor S1P protects against chemotherapy-induced damage to the primordial follicle pool, and ascertain whether the mechanism involves direct effects on primordial follicles via S1P receptors, or protection of ovarian microvasculature. These aims will be studied in short-and long-term xenograft models where not only the primordial follicle survival but the potential of S1P- protected primordial follicles to develop into antral stages and produce competent oocytes will be tested.

描述（由申请人提供）：化疗引起的卵巢功能衰竭是一个日益严重的公共卫生问题，对生活质量产生重大影响。如果已知化疗药物的个体毒性，可以就卵巢损伤的可能性和保留生育能力的必要性向患者提供咨询。此外，如果开发出药物性卵巢保护策略，则无需通过手术干预来保留生育能力，从而降低伴随的风险和成本。该项目的长期目标是通过开发更准确的卵巢储备评估策略和异种移植模型来提高我们对化疗引起的卵巢衰竭风险的了解，此外还测试在异种移植模型中预防化疗引起的卵巢储备损伤的药理学方法的有效性。该提案的重点是乳腺癌，因为它是年轻女性中最常见的恶性肿瘤。具体目标是：（1）利用现有和新兴的卵泡群标志物确定常用乳腺癌化疗方案对卵巢储备的影响。化疗前和化疗后将进行窦卵泡计数、抑制素 B、抗苗勒氏管激素和 FSH/雌二醇测量，并进行 2.0-4.5 年的随访。 (2)测定化疗药物对人卵巢损伤的程度并确定其机制。具有人类卵巢组织异种移植物的免疫缺陷小鼠将使用常用和新兴的药物或载体进行治疗；卵泡密度的变化以及通过预裂解的 caspase-3 表达量化的凋亡卵泡死亡的程度将用于衡量影响。微血管损伤导致卵泡损失的另一种机制也将通过定量血管评估方法和活体染料注射进行研究。此外，我们将通过分析参与 DMA 修复的 ATM 途径蛋白来研究是否在存活的原始卵泡中诱导双链 DMA 断裂。 (3) 确定细胞死亡抑制剂S1P是否可以防止化疗引起的原始卵泡池损伤，并确定其机制是否涉及通过S1P受体对原始卵泡的直接影响，或保护卵巢微血管系统。这些目标将在短期和长期异种移植模型中进行研究，其中不仅将测试原始卵泡的存活率，而且将测试S1P保护的原始卵泡发育成窦期并产生有能力的卵母细胞的潜力。