Nature Medicine
3, 1228 - 1232 (1997)
doi:10.1038/nm1197-1228
Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destructionGloria I. Perez1, C. Michael Knudson2, Lucy Leykin1, Stanley J. Korsmeyer2
& Jonathan L. Tilly1, 3
1Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics and Gynecology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA
2Howard Hughes Medical Institute and Division of Molecular Oncology, Departments of Medicine and Pathology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8022, St. Louis, Missouri 63110, USA
3Correspondence should be addressed to J.L.T. 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.
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