Abstract #3990: The pan-Bcl-2 family inhibitor ABT-737 synergizes with DNA damaging agents by enhancing apoptosis in acute lymphoblastic leukemia cells

Background: DNA damaging agents are the most common chemotherapy for human cancers, and combining them with agents that modulate resistance mechanisms can enhance activity. Etoposide, cyclophosphamide, and doxorubcin are DNA-damaging agents that are employed against a variety of cancers including recurrent pediatric acute lymphoblastic leukemia (ALL). We determined if the BH-3 mimetic pan-Bcl-2 inhibitor ABT-737 could enhance the cytotoxicity of DNA damaging agents in ALL cell lines. Methods: Cytotoxicity was determined using a fluorescence-based digital imaging assay (DIMSCAN). Changes in various proteins were detected by immunoblotting. Apoptotic cells were detected by flow cytometry using Annexin-V and propidium iodide. Mutational status of TP53 was evaluated by sequencing PCR amplified DNA. Results: Combining ABT-737 with etoposide, cyclophosphamide (as 4-HC), or doxorubicin caused synergistic cytotoxicity (combination index values: Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3990.