APOPTOSIS-ASSOCIATED SIGNALING PATHWAYS ARE REQUIRED FOR CHEMOTHERAPY-MEDIATED FEMALE GERM-CELL DESTRUCTION

Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show tha t unfertilized mouse oocytes exposed to therapeutic levels of the anti tumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when t reated with DXR. Apoptosis induced by DXR in oocytes is blocked by sph ingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oo cytes from Bax-deficient, but not p53-null, female mice display comple te resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatm ent of oocytes with a specific peptide inhibitor of caspases also abro gates the apoptotic response to DXR. These findings indicate that oocy te destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.