Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
PLoS One. 2013 Jul 29;8(7):e70117. doi: 10.1371/journal.pone.0070117. Print 2013.
Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.
Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.
Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.
Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to.
在绝经前妇女中，化疗治疗与卵泡丢失和卵巢早衰有关；其确切机制尚不确定。在这里，将两种常用的化疗药物（顺铂和阿霉素）添加到小鼠卵巢培养系统中，以比较导致生殖细胞丢失的事件顺序。还检查了甲磺酸伊马替尼保护卵巢免受顺铂或阿霉素引起的卵巢损伤的能力。
新生小鼠卵巢共培养 6 天，在第 2 天暴露于化疗药物：这允许检查卵泡发育的最早阶段。用 cleaved PARP 和 TUNEL 检测药物处理后的细胞凋亡。将伊马替尼添加到顺铂和阿霉素的培养物中，以确定任何保护作用。
顺铂处理的卵巢组织学分析显示卵母细胞特异性损伤；相比之下，阿霉素优先引起颗粒细胞损伤。cleaved PARP 的表达明显增加，顺铂（16 倍，p<0.001）和阿霉素（3 倍，p<0.01）。TUNEL 染色显示两种药物对原始卵泡损伤的证据很少。伊马替尼对顺铂诱导的卵泡损伤具有显著的保护作用（p<0.01），但对阿霉素治疗没有作用。
顺铂和阿霉素均可引起卵巢损伤，但模式明显不同，伊马替尼可保护卵巢免受顺铂损伤，但不能免受阿霉素损伤。任何旨在阻断化疗药物对卵巢影响的治疗方法可能需要针对患者暴露的药物（s）。
