Perez G I, Knudson C M, Leykin L, Korsmeyer S J, Tilly J L
Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics and Gynecology, Harvard Medical School, Boston 02114, USA.
Nat Med. 1997 Nov;3(11):1228-32. doi: 10.1038/nm1197-1228.
Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.
化疗导致的卵母细胞破坏所引起的雌性不育是一种不幸的，而且在许多情况下是不可避免的后果。我们发现，暴露于治疗水平的抗肿瘤药物阿霉素（DXR）的未受精小鼠卵母细胞会发生凋亡；然而，受精的卵母细胞在用DXR处理时不会启动凋亡，而是进入细胞周期停滞状态。鞘氨醇-1-磷酸（一种神经酰胺促进的细胞死亡抑制剂）可阻断DXR在卵母细胞中诱导的凋亡。来自Bax基因缺陷（而非p53基因缺失）雌性小鼠的卵母细胞在体内和体外对DXR诱导的凋亡均表现出完全抗性。用半胱天冬酶的特异性肽抑制剂预处理卵母细胞也可消除对DXR的凋亡反应。这些发现表明，通过操纵凋亡相关信号通路可以预防化疗引起的卵母细胞破坏。
