Tanaka Toshiko, Kurokawa Hideo, Matsuno Koji, Matsumoto Shinobu, Hayashida Yutaka
Division of Multidisciplinary Studies, Department of Bioscience, Kyushu Dental College, 2-6-1 Manazuru, Kokura-kitaku, Kitakyushu 803-8580, Japan.
Anticancer Res. 2008 Sep-Oct;28(5A):2663-8.
The cytotoxic activity of bleomycin (BLM) was evaluated in cisplatin (CDDP)-sensitive (A2780) and -resistant (2780CP) human ovarian cancer cells, and the mechanism of increased antitumor activity of BLM in the 2780CP cells was investigated. Compared with the A2780 cells, the 2780CP cells exhibited a 4.5-fold increase in resistance to CDDP, but were 4.0-fold more sensitive to BLM. The cellular glutathione (GSH) levels in the 2780CP cells were significantly higher than those in the A2780 cells, however, GSH depletion in the 2780CP cells below the levels in the A2780 cells by using buthionine-[S,R]-sulfoximine (BSO) did not affect the sensitivity to BLM. BLM decreased 5-bromo-2'-deoxyuridine (BrdU) incorporation after 24-h exposure by 27.5%-90% compared to that of the untreated control at BLM doses of 25-500 ng/ml in the 2780CP cells, but only by 1.5% -45.8% in the A2780 cells. Furthermore, in the 2780CP cells, the percentage of S-phase cells markedly decreased, with an increase in G2/M-phase cells as determined by flow cytometry after exposure to BLM. The enhanced cytotoxity of BLM in CDDP-resistant 2780CP cells could be attributed to BLM-induced G2/M accumulation and significantly inhibited DNA synthesis, not to increased cellular GSH levels.
对博来霉素（BLM）在顺铂（CDDP）敏感（A2780）和耐药（2780CP）的人卵巢癌细胞中的细胞毒性活性进行了评估，并研究了BLM在2780CP细胞中抗肿瘤活性增强的机制。与A2780细胞相比，2780CP细胞对CDDP的耐药性增加了4.5倍，但对BLM的敏感性高4.0倍。2780CP细胞中的细胞内谷胱甘肽（GSH）水平显著高于A2780细胞，然而，使用丁硫氨酸-[S，R]-亚砜胺（BSO）将2780CP细胞中的GSH消耗至低于A2780细胞中的水平，并不影响对BLM的敏感性。在2780CP细胞中，当BLM剂量为25-500 ng/ml时，24小时暴露后BLM使5-溴-2'-脱氧尿苷（BrdU）掺入量比未处理对照降低了27.5%-90%，但在A2780细胞中仅降低了1.5%-45.8%。此外，在2780CP细胞中，经BLM处理后，通过流式细胞术测定，S期细胞百分比显著降低，G2/M期细胞增加。BLM在CDDP耐药的2780CP细胞中增强的细胞毒性可归因于BLM诱导的G2/M期积累和显著抑制的DNA合成，而非细胞内GSH水平的增加。
