G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

Christopher M. Sturgeon and Michel Roberge

volume 6 | issue 5

1 March 2007
Pages: 572 - 575

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Chemical inhibitors of the G2 checkpoint can sensitize p53-defective cancer cells to DNA damage and several are in preclinical or clinical development. These compounds are commonly thought to increase killing at the G2/M transition by forcing cells to divide with unrepaired DNA. We examined the effects of the ATM/ATR inhibitor caffeine and the Chk1 inhibitor isogranulatimide on the clonogenic survival of two p53-defective cell lines, MCF7-mp53 and HCT-116 p53-/- cells, when added at different times after exposure to ionizing radiation. Exposure 16-24 h after irradiation, when G2 arrest is maximal, forced premature entry into mitosis but increased clonogenic survival. Radiosensitization occurred mostly upon exposure between 2 and 16 h after irradiation, correlating with S-phase traversal. These results suggest that inhibition of the S phase activities of ATM/ATR and Chk1 may be more relevant to radiosensitization of p53-defective cells than G2 checkpoint abrogation and that careful scheduling of combination treatments might be required for synergistic antitumour effects in vivo.

Authors

Christopher M. Sturgeon

University of British Columbia, Vancouver, British Columbia, Canada

Michel Roberge

University of British Columbia, Vancouver, British Columbia, Canada

We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link: