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The use of genotoxic agents in the treatment of leukemia is often met with treatment failure due to the development of cellular resistance. Reliance on DNA structure checkpoints and downregulation of the apoptotic response allow malignant cells to repair chromosomal damage prior to mitosis, thus avoiding the activation of cell death pathways. Abrogation of checkpoint function may reverse this form of treatment resistance. We have evaluated the effect of Chk1 / Chk2 inhibition alone and in combination with genotoxic agents in three B-CLL leukemic cell lines. We find that Chk kinase inhibition results in an anti-proliferative phenotype, and that this treatment potently synergizes with multiple genotoxic agents to promote cell death. Measured synergy was highest with agents active in S and G2 phases of the cell cycle, and was accompanied by biochemical and phenotypic features consistent with mitotic catastrophe. Use of Chk kinase inhibitors in combination with standard genotoxic therapies may be an effective approach to treatment of leukemia and other neoplasms.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA