DNA damage detected with γH2AX induced by anticancer drugs on ovarian clear cell carcinoma

用组蛋白H_2AX(γH_2AX)磷酸化检测卵巢透明细胞癌、子宫体子宫内膜样腺癌和宫颈鳞癌三种抗癌药物所致DNA损伤的发生率和类型的差异。卵巢透明细胞癌：顺铂作用后，S期细胞DNA损伤频繁，耐药细胞周期停滞于G1、G2/M期，γ-H_2AX无明显增加。两种细胞对顺铂和卡铂(CBDCA)的敏感性不同。紫杉醇的抗肿瘤作用是通过G2/M期阻滞诱导的，与卡铂联合作用可能是有效的。这是日本首次以γH_2AX为指标，通过细胞周期与DNA损伤之间的关系来评价抗癌药物的抗肿瘤活性。免疫细胞化学方法在…中的应用此外，本研究还检测到了γH_2AX，这表明即使在非常低的浓度下也会出现DNA损伤，而且灵敏度很高。因此，一种很有前景的方法可以方便、快速地识别可能对CCC有效的药物。2.子宫体子宫内膜样腺癌：研究表明，不同细胞系在药物治疗后DNA损伤与细胞周期特异性、诱导细胞凋亡或衰老方面存在显著差异。阿霉素(DOX)对γH_2AX的诱导作用没有明显的细胞周期特异性，其作用机制可能与其他因素调节的氧化损伤机制类似。顺铂和5-氟尿嘧啶(5-FU)处理后，S期细胞中H_2AX优先被磷酸化，这与复制应激的诱导一致。与其他细胞系相比，表达wtP53的Ishikawa细胞的反应不同。这些数据表明，使用这些药物治疗子宫内膜样腺癌可能必须针对个别患者进行定制。较少

Differences in the incidences and types of DNA damage induced by antitumor agents for clear cell carcinoma (CCC) of the ovary, endometrioid adenocar cinoma of the uterine corpus, and squamous cell carcinoma of the cervix were determined using phosphory- lation of histon H2AX (γH2AX).1. Clear cell adenocarcinoma of the ovary (CCC): After administration of cisplatin(CDDP), DNA damage was frequent in S -phase cells, while cell-cycle arrest occurred in the G1 and G2/M phases and γH2AX did not increase in CDDP-resistant cells. Sensitivities to CDDP and carboplatin(CBDCA) differed between the two cell lines. The antitumor effect of paclitaxel(PTX) is induced by G2/M arrest, and combination treatment with CBDCA, inducing DNA damage in G2/M-phase cells, might be effective.This is the first study in Japan to evaluate the antitumor activity of anticancer agents by focusing on the relationship between the cell cycle and DNA damage using γH2AX as an indicator. The immunocytochemical method used in … More this study detects γH2AX, which indicates DNA damage even at very low concentrations and with high sensitivity. Therefore, a promising method of easily and rapidly identifying agents potentially effective against CCC. 2.Endometrioid adenocarcinoma of the uterine corpus: The study revealed significant differences among the cell lines in the effects of DNA damage vis-a-vis cell cycle phasespecificity, induction of apoptosis or senescence following drug treatment. doxorubicin (DOX) treatment showed little cell cycle specificity in terms of induction of γH2AX, and its mechanism, which is similar to another anthracycline DNA topoisomerase II inhibitor mitoxantrone, may involve oxidative DNA damage modulated by other factors. Treatment with CDDP and 5-fluorouracil (5-FU) led to phosphorylation of H2AXpreferentially in S -phase cells, consistent with the induction of replication stress. The response of Ishikawa cells expressing wt p53 was different compared to other cell lines. The data suggest that the treatment of endometrioid adenocarcinoma with these drugs may have to be customized to individual patients. Less