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Abrogation of the G₂ Checkpoint Results in Differential Radiosensitization of G₁ Checkpoint-deficient and G₁ Checkpoint-competent Cells¹

Department of Radiation Oncology RC-08, University of Washington School of Medicine, Seattle, Washington 98195 [K. J. R., L. W. W., M. G.]; Fred Hutchinson Cancer Research Center, Seattle, Washington 98104 [G. W. D., D. A. G., M. G.]; and Texas Children's Hospital, Houston, Texas 77030 [S. E. P.]

We have examined the effect of abrogation of the G₂ checkpoint on the radiosensitivity of G₁ checkpoint-proficient and G₁ checkpoint-deficient cells. A549 human lung adenocarcinoma cells were transduced with the E6 oncogene of the human papillomavirus type 16 to eliminate their radiation-induced G₁ arrest. These E6+ cells exhibited a dose-dependent increase in radiation resistance compared to control A549 cells transduced with the vector alone. Treatment (96 h) with 2 mM caffeine resulted in an abrogation of the cellular G₂ checkpoint in both E6+ and control cells and a differential radiosensitizing effect on the two cell lines such that the E6+ clones and the vector controls became equally radiosensitive. These data show that human tumors which are radioresistant due to the loss of the p53-mediated G₁ checkpoint can be made radiosensitive by abrogation of the G₂ checkpoint. The implications of these results for cancer therapy are discussed.

¹ This research supported by Grant RO1-CA58954 from the NIH and by funds from the Center for Radiation Research.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology RC-08, University of Washington Hospital, School of Medicine, Seattle, WA 98195.

Received 1/19/95. Accepted 2/22/95.

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