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: 7658958
• 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/7658958
• 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 Drug Therapy; Complication; Counseling; Cyclophosphamide; DNA Repair Gene; Data; Doxorubicin; Dyes; Effectiveness; Endocrine; Estradiol; Failure; Fertility; 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; docetaxel; follow-up; improved; inhibin B; inhibitor/antagonist; malignant breast neoplasm; mullerian-inhibiting hormone; patient population; 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）：化学疗法引起的卵巢衰竭是日益增长的公共卫生问题，对生活质量产生了重大影响。如果知道化学疗法剂的个体毒性，可以就卵巢损伤的可能性和生育能力保存的可能性进行咨询。此外，如果制定了药理学卵巢保护策略，将不需要手术干预措施来保留生育能力，从而降低了伴随的风险和成本。该项目的长期目标是通过制定更准确的卵巢储备评估策略和异种养殖模型来提高我们对化学疗法引起的卵巢衰竭风险的理解，此外还测试了药理学方法的有效性，以防止化学疗法在Xenograpt模型中诱导化学疗法诱导对卵巢储备的损害。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。具体目的是：（1）使用卵泡种群的现有和新兴标记来确定常用乳腺癌化学疗法方案对卵巢储备的影响。腹部卵泡计数，抑制素-B，抗毛刺激素和FSH/雌二醇测量将通过2.0 - 4.4.5岁的随访获得前后的化学后治疗。 （2）测量程度并确定人类卵巢化学治疗剂引起的损伤机制。与人卵巢组织异种移植物的免疫缺陷小鼠将用常用和新兴剂或媒介物治疗；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。微血管损伤的卵泡损失的另一种机制也将通过定量血管评估方法和重要的染料注射来研究。此外，我们将通过分析与DMA修复有关的ATM途径蛋白分析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是否可以防止化学疗法诱导的原始卵泡池的损害，并确定该机制是否涉及通过S1P受体对原始卵泡的直接影响，或保护卵巢微腔。这些目标将在短期和长期的异种移植模型中进行研究，其中不仅原始卵泡存活率，而且S1P受保护的原始卵泡的潜力将发展为肛门阶段并产生有效的卵母细胞。