BCL-2 AND BCL-XL CAN DIFFERENTIALLY BLOCK CHEMOTHERAPY-INDUCED CELL-DEATH

Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors an d their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and gamma-irradiation. In the pres ent report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if thes e survival proteins could provide equivalent protection when challenge d with chemotherapy or gamma-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposid e-induced cell death. In addition, Bcl-XL provided significantly great er cell viability than Bcl-2 against methotrexate, fluorouracil, and h ydroxyurea, three S-phase specific agents. In apoptosis induced by gam ma-irradiation and cisplatin, two antitumor treatments that are cell-c ycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against gamma-irradiation, but Bcl-XL provided better prot ection than Bcl-2 against cisplatin. These results indicate that Bcl-X L and Bcl-2 confer a differential ability to protect against chemother apy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase speci ficity. (C) 1997 by The American Society of Hematology.