Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides.

Bcl-2 is an attractive target for anticancer therapy in a number of malignancies, as its expression is associated with inhibition of the apoptotic program and resistance to traditional therapeutic agents. Bcl-2 antisense therapy with G3139 (oblimersen sodium; Genasense, Genta Inc, Berkeley Heights, NJ) is in clinical trials for a number of malignancies, including an ongoing trial in myeloma. In vitro G3139 has been shown to downregulate Bcl-2 in myeloma cells, sensitizing them to chemotherapeutic agents. We have undertaken a project to evaluate antisense inhibition strategies in Waldenstrom's macroglobulinemia (WM), and whether the Bcl-2 pathway may provide a therapeutic target in this disease. We have shown that Bcl-2 is expressed in WM cells in vitro and that downregulation of Bcl-2 may be achieved by treatment with G3139. Treatment of WM cells with G3139 is associated with increased cell death and shows potential synergy with chemotherapeutic agents active in WM. Bcl-2 downregulation via G3139 antisense treatment may have potential anticancer efficacy in WM and further studies to address its effects on clinical specimens are warranted, in anticipation of using this agent in WM clinical trials.