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医学博士 甲第927号 平成16年3月31日 （埼玉医科大学）
Role of Reactive Oxygen Species as an Anticancer Effect Induced by 5-Fluorouracil
− Experimental Study Using a Human Gastric Cancer Cell Line (MKN45) −
Kairyu Kaai (Department of General and gastroenterological Surgery, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
It is well known that in a variety of anticancer agent, such as Mitomycin C, Adriamycin, CDDP, reactive oxgen species (ROS) play important roles in cytotoxic effects to tumor cells. However, as to 5-fluorouracil (5-FU) it has not been clear whether ROS can be induced by 5-FU or not and its related to anticancer effect. Therefore, in order to clarify the role of ROS in cytotoxic process induced by 5-FU, we measured ROS and 8-oxoguanidine (8-OHdG) of 5-FU-treated MKN-45 (human poorly differentiated adenocarcinomatous cells of stomach) and HUVEC (Human umbilical vein endothelial cells) cell lines by flow cytometry. In addition, the relation between ROS and apoptosis was investigated by flow cytometry. Trend of various enzymes related to active oxygen and promoting / inhibiting factors of apoptosis also measured by Western blotting method. Levels of ROS and 8-OHdG(specific maker of DNA damage caused by ROS) increased in MKN-45 cells exposed to CDDP or 5-FU, ROS were increased, whereas 8-OHdG showed no change in HUVEC cells. Level of SOD and p22 proteins increased, whereas catalase showed no change in MKN-45 cells exposed to 5-FU. Although DNA degradation induced by ROS via p53 and NFκB enhancement was found in MKN-45 cells exposed to 5-FU. There are no effect of caspase-dependent apoptotic factors. In summery, our results may indicate that anticancer effect of 5-FU is mediated mainly through the caspase-independent apoptosis via the ROS induction.