Inhibition of radiation-induced DNA dsbs repair by inducing misrejoining and its clinical application

点击翻译按钮获取中文摘要

The purpose of this study was to inhibit repair of radiation-induced DNA damages in malignant cells by using siRNA for ATM gene and other chemical components. To achieve this purpose, we designed in-vitro and in-vivo experiments. When exponentially growing normal and cancer cells were treated with sIRNA for ATM gene, radiation-sensitivity was enhanced. However, when non-cycling normal cells (GO) cells were treated with siRNA before irradiation, no significant change in sensitivity was observed, suggesting that siRNA may not work on non-cycling cells. To study the effect of siRNA in vivo, Hela cells (human uterine cancer cells) was transplanted to Balb/c nu/nu mice. After two weeks, ATM siRNA (12 nM) was injected directly and 24 - 72 hour later tumors were irradiated with X-rays. It was found that the maximum effect was observed when siRNA was injected around 48 hour before irradiation. Lb study synergistic effect of ATMsiRNA with radiation, mice tumors were irradiated with 4 Gy per day up to total dose of 20 Gy. During this treatment, siRNA was injected twice, I.e, 24 hour before irradiation and after second irradiation. The tumor volume was compared with non-treated mice. It was found after 21 day, tumor size was found to increase up to 6.5 times for non-irradiated mice, 4.5 times for only irradiation group and 3 times for mice treated with siRNA with irradiation. Further study was underway by using ATM specific inhibitor to understand the function of ATM gene for radiation-repair pathway.