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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

VX-765对化疗所致卵巢损伤小鼠有保护作用

卷 23, 期 4, 2023

发表于: 21 October, 2022

页: [307 - 318] 页: 12

弟呕挨: 10.2174/1568009622666220930110024

open access plus

摘要

背景：恶性肿瘤仍然是一个主要的全球公共卫生问题。近40年来，由于恶性肿瘤患者的多学科综合治疗方案，特别是化疗方案的进步，大大提高了恶性肿瘤患者的生存率。在恶性肿瘤治疗成功后，这组患者有望保持生育能力或恢复内分泌功能。因此，关注化疗对育龄妇女卵巢的损害对于保护她们的生育能力和提高她们的生活质量至关重要。 目的：本研究试图评价VX-765在小鼠模型化疗引起的卵巢损伤中是否具有卵巢保护作用。 方法:雌性C57BL/6J小鼠灌胃VX-765，每日1次，连续灌胃21 d。最后一次灌胃VX- 765一周后开始使用环磷酰胺(Cy)。然后对各组不同水平的卵泡进行详细分类。利用免疫组织化学和Western blot分析卵巢中关键蛋白(FOXO3a、mTOR、RPS6和AKT)的表达及其对PI3K / PTEN / AKT通路的磷酸化情况。ELISA法测定AMH浓度。 结果:各水平Cy处理小鼠卵泡数量均低于正常组(P < 0.05)。同时，在接受Cy治疗前接受VX-765治疗的小鼠比仅接受Cy治疗的小鼠有更多的原始卵泡(PMF) (P < 0.05)。在早期生长卵泡(EGF)和窦性卵泡(AF)中，各组间差异无统计学意义(P > 0.05)，但均低于正常组(P < 0.05)。连续Cy处理小鼠中，联合VX-765 (C-Cy-Vx765)小鼠的总卵泡数(TF)高于未加VX-765的小鼠，而两组小鼠的TF均低于正常组(P < 0.05)。C-Cy-Vx765组PMF/TF显著高于其他3组，EGF/TF显著低于其他3组(P < 0.05)。免疫组化结果显示，在Cy处理的小鼠中，PI3K / PTEN / AKT通路主要蛋白的磷酸化形式更为阳性。Western blot分析表明，当Cy和VX-765联合处理时，这些磷酸化蛋白的增加水平与Cy单独处理时相比有所下降。Cy和VX-765联合治疗小鼠的AMH水平明显高于正常小鼠(P < 0.05)。小鼠性成熟后，Cy和VX- 765联合处理小鼠AMH水平仍高于Cy处理小鼠(P < 0.05)，与正常小鼠无显著差异(P > 0.05)。 结论:VX-765能维持AMH水平，抑制PMF的募集，从而保护小鼠免受Cy诱导的促性腺毒性。因此，VX-765可能在化疗引起的卵巢损伤小鼠中发挥保护作用。

关键词: VX-765，环磷酰胺，卵巢损伤，卵巢保护，PI3K / PTEN / AKT通路，烧毁。

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图形摘要

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