Overexpression of Bcl-x(L) promotes chemotherapy resistance of mammary tumors in a syngeneic mouse model

Bcl-x(L), a prosurvival member of the Bcl-2 family that is expressed in man y tumors, represses apoptosis induced:by chemotherapeutic drugs ill vitro. However, the contribution of apoptosis and prosurvival Bcl-2-related protei ns to chemotherapy resistance in vivo is unknown and has been challenged by recent results with clonogenic survival assays. To test the ability of Bcl -x(L) to provide chemotherapy resistance to tumors, we transfected the mous e bcl-x(L) gene into the tumorigenic SCK mammary cell. line and assessed th e response of tumor cells to chemotherapeutic drugs in clonogenic assays an d in a syngeneic mouse model. Bcl-x(L) conferred protection on SCK cells ag ainst methotrexate at certain drug concentrations, but not at all against 5 -fluorouracil in clonogenic survival assays in vitro. Injection of SCK cell s transfected with Bcl-x(L) or control plasmid in the mammary fat pads of s yngeneic recipient mice resulted in tumors of similar size. However, althou gh the volume of control tumors regressed up to 80% after 4 to 5 days of ch emotherapy, SCK tumors expressing Bcl-x(L) did not regress and continued to grow in the presence of methotrexate or 5-fluorouracil. In addition, numbe rs of apoptotic cells were significantly higher in control tumors as compar ed to Bcl-x(L)-expressing tumors in animals treated with methotrexate or 5- fluorouracil. These results provide evidence that inhibition of apoptosis t hrough Bcl-x(L) overexpression can promote resistance to chemotherapy in tu mors in vivo.