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Study on mechanism of enhancing tumor radiosensitivity by sorafenib in colorectal cancer

Other Titles
 대장암에서 소라페닙의 방사선민감성 증진 기전에 관한 연구 
 Dept. of Radiation Oncology (방사선종양학교실) 
Issue Date
Dept. of Midicine/박사
Sorafenib, an orally available multikinase inhibitor, is effective for the treatment of patients with advanced renal cell carcinoma and those with unresectable hepatocellular carcinoma. Even though many molecular targeted agents with anti-angiogenic activity have been demonstrated to enhance tumor radiosensitivity, there has been no positive data about the synergistic interaction between sorafenib and radiation until now. In this study, I investigated the mechanism of sorafenib-induced enhancement of radiosensitivity. The effects of sorafenib on in vitro radiosensitivity of DLD-1 and HT-29 (colon cancer) cell lines were evaluated using clonogenic assay. The impact of sorafenib on radiation-induced cell cycle kinetics and on apoptosis was analyzed using flow cytometry. Extracellular-signal-regulated kinases (ERK) signaling was examined by Western blot analysis. DNA damage and repair were evaluated using gamma histone H2AX (γ-H2AX). Tumor growth delay was used to evaluate the effects of sorafenib on in vivo (DLD-1) tumor radiosensitivity. Exposure of each cell line to sorafenib combined with irradiation resulted in an increased radiosensitivity with dose enhancement factors at a surviving fraction of 0.25 ranging from 1.21 to 1.61. Sorafenib and radiation induced accumulation of tumor cells in G2-M phase, but had no effect on radiation-induced apoptosis and phosphorylation of ERK. As a measure of DNA double strand breaks, γ-H2AX foci were determined as a function of time after irradiation plus sorafenib combination. Exposure to sorafenib and radiation resulted in a greater number of γ-H2AX foci than radiation alone. In vivo tumor xenograft studies confirmed that administration of sorafenib results in significant tumor growth inhibition when combined with radiation. These results indicate that sorafenib enhances tumor radiosensitivity in colorectal cancer, and suggest that this effect was induced from prolongation of G2-M arrest through DNA damage.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 3. Dissertation
Yonsei Authors
Kim, Yong Bae(김용배) ORCID logo https://orcid.org/0000-0001-7573-6862
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