並列タイトル等食道癌細胞株における5-フルオロウラシルにより誘導されるDNA障害へのリボヌクレオチドリダクターゼM1の関与
学位博士(医学)
Philosophy in Medical Science
一般注記5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the rate?limiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus forma-tion, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus forma-tion induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.
YOSHIRO AOKI, KENJI SAKOGAWA, JUN HIHARA, MANABU EMI, YOICHI HAMAI, KAZUTERU KONO, LIN SHI, JIYING SUN, HIROYUKI KITAO, TSUYOSHI IKURA, HIROYUKI NIIDA, MAKOTO NAKANISHI, MORIHITO OKADA and SATOSHI TASHIRO; Involvement of ribonucleotide reductase-M1 in 5-fluorouracil-induced DNA damage in esophageal cancer cell lines; INTERNATIONAL JOURNAL OF ONCOLOGY 42: 1951-1960, 2013 (DOI: 10.3892/ijo.2013.1899)
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