ATM inhibitors에 의한 방사선 민감도 증진

초록

The purpose of this study was to find the possibility of using ATM targeted agents for tumor cell radiosensitization. ATM plays central role in response of cells to DNA damaging agents and involved in cell cycle arrest and DNA damage repair in irradiated cells. ATM has been known to activate and stabilize p53 in response to radiation. There are several ATM inhibitors such as caffeine, pentoxifylline, and wortmannin. We studied the effect of these inhibitors using the human colorectal cancer RKO.C cells, RKO/ATM, which is ATM overexpressed, and human lung adenocarcinoma A549 cells. RKO.C cells were irradiated in the presence of caffeine, pentoxifylline or wortmannin, and then the kinetics of G2/M arrest, apoptosis and clonogenic survival were analyzed. Clonogenic survival decreased to 0.01% after 9 Gy irradiation and further decreased to 0.001% when cells were treated with 3 mM of caffeine and irradiation with 9 Gy. The effect of 1 mM of pentoxifylline of 10μM of wortmannin to enhance the radiation effect was far less than that of 3 mM of caffeine. Gene expression was examined using human 10k chip in RKO and RKO/ATM after irradiation. One hundred thirty five known genes and 15 unknown genes were differentially expressed between RKO and RKO/ATM after irradiation. We observed that caffeine significantly inhibits ATM kinase activities in RKO/ATM cells after irradiation.