Abstract #4600: Chk1 inhibitors override the DNA damage checkpoint and enhance anti-tumor activity of irinotecan in p53-deficient tumor xenografts in mice
2009
DNA damage can activate both Chk1- and p53-mediated checkpoints which function independently to prevent cells from entering mitosis and subsequent mitotic catastrophe by enforcing cell cycle arrest. In p53-deficient cells, the control of the progression into mitosis in response to DNA damage relies solely on the Chk1-mediated checkpoint and thus the inhibition of Chk1 could selectively sensitize p53-deficient cancer cells to mitotic catastrophe. Chk1 inhibitors have been developed as p53-dependent chemosensitizers. We have evaluated the checkpoint-abrogating and anti-tumor activities of several potent and specific Chk1 inhibitors in a mouse tumor xenograft model. When administered in combination with irinotecan, Chk1 inhibitors promoted mitotic entry in p53-deficient tumors but not in p53-competent tumors as measured by the quantification of phospho-histone H3 using an immunohistochemistry assay. In addition, while Chk1 inhibitors alone lack anti-tumor activity, they can synergize with irinotecan to suppress tumor growth. The enhancement of anti-tumor effect by Chk1 inhibitors is affected by the dose of irinotecan as well as the dosing schedule. Furthermore, we determined the minimum duration of Chk1 inhibition and the optimal dosing schedule required for promoting mitotic entry and augmenting the suppression of tumor growth using the osmotic minipump to dose Chk1 inhibitors. We found that ~ 6-hour inhibition of Chk1 was needed to abrogate the checkpoint function and enhance anti-tumor efficacy and that administration of Chk1 inhibitors subsequent to irinotecan displayed stronger synergistic effect than co-administration of two agents. These results provide guidance to the clinical development of Chk1 inhibitors. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4600.
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