Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells.
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.
Russell
K J
KJ
Department of Radiation Oncology RC-08, University of Washington School of Medicine, Seattle 98195, USA.
Wiens
L W
LW
Demers
G W
GW
Galloway
D A
DA
Plon
S E
SE
Groudine
M
M
D000230:Adenocarcinoma; D002110:Caffeine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D005814:Genes, Viral; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D015739:Nocodazole / Q000494:pharmacology; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D011838:Radiation-Sensitizing Agents; D002110:Caffeine; D015739:Nocodazole