Optimizing chemotherapy for transitional cell carcinoma by application of bcl-2 and bcl-xL antisense oligodeoxynucleotides
Optimizing chemotherapy for transitional cell carcinoma by application of bcl-2 and bcl-xL antisense oligodeoxynucleotides
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DOI：
10.1016/j.urolonc.2007.01.017
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发表时间：
2007-11-01
影响因子：
2.7
通讯作者：
Michel, Maurice Stephan
中科院分区：
文献类型：
--
作者：
Bolenz, Christian;Becker, Andreas;Michel, Maurice Stephan
目的：移行细胞癌(TCC)经膀胱内和全身化疗后的治疗失败率仍然较高。抗凋亡蛋白如Bcl2和Bclxl被报道促进了TCC的化疗耐药。反义寡核苷酸(AS-ODN)靶向bcl2和bclxl信使核糖核酸可增强化疗药物的细胞毒作用。因此。方法和材料：用免疫印迹或免疫组织化学方法检测顺铂、吉西他滨、丝裂霉素C和紫杉醇单独作用后，人TCC细胞系中bcl2和bclxl的表达。另外，bcl2或bclxl反义寡核苷酸与每种化疗药物联合应用。用标准的四甲基偶氮唑盐比色法和诺氏血细胞分析仪检测细胞存活率。结果：所有细胞株对单一化疗药物的反应呈剂量依赖关系。单用顺铂、吉西他滨、丝裂霉素Q和紫杉醇的最高细胞死亡率分别为47.4%、39.0%、83.4%和54.8%。化疗与bcl2或bclxl反义寡核苷酸联合作用后，HT1197细胞死亡率显著升高(例如，紫杉醇与bclxl反义寡核苷酸合用的细胞死亡率分别为30.3%和87.2%)。三因素方差分析显示联合作用对所有细胞株均有显著影响。结论：我们的研究证实bcl2和bclxl反义寡核苷酸的联合作用增强了化疗药物对TCC细胞株的细胞毒作用。在体外和体内模型中还需要进行进一步的试验，以促进患者的临床应用。(C)2007 Elsevier Inc.保留所有权利。
Objective: Therapy failure after intravesical and systemic chemotherapy for transitional cell carcinoma (TCC) is still high. Antiapoptotic proteins such as Bcl-2 and Bcl-xL have been reported to promote chemoresistance in TCC. Targeting bcl-2 and bcl-xL messenger ribonucleic acid with antisense oligodeoxynucleotides (AS-ODNs) may enhance the cytotoxic effects of chemotherapeutic agents. Therefore. we investigated the effects of bcl-2 and bcl-xL AS-ODNs in combined treatment with conventional and new chemotherapeutic agents to evaluate the cytotoxic effects in comparison to monotreatment.Methods and materials: Western blot analysis or immunohistochemistry verified Bcl-2 and Bcl-xL expression in a panel of human TCC cell lines that had been monotreated with cisplatin, gemcitabine, mitomycin C, and paclitaxel. In addition, bcl-2 or bcl-xL AS-ODNs were applied in combination with each chemotherapeutic agent. Cell viability was determined using a standard MTT assay and Neubauer hemocvtometry.Results: All cell lines responded to chemotherapeutic monotreatment in a dose-dependent manner. Maximum cell death rates after monotreatment were 47.4% (cisplatin), 39.0% (gemcitabine), 83.4% (mitomycin Q, and 54.8% (paclitaxel). After combined treatment with chemotherapy and bcl-2 or bcl-xL AS-ODNs, cell death rates were significantly higher (e.g., 30.3% vs. 87.2% in HT 1197 cells for monotreatment vs. the combination of paclitaxel and bcl-xL AS-ODNs). Three-way analysis of variance revealed that combined treatment had a significant effect on all cell lines.Conclusions: Our study confirms that the addition of bcl-2 and bcl-xL AS-ODNs enhances the cytotoxic potential of chemotherapeutic agents in TCC cell lines as a result of combined effects. Further trials in ex vivo and in vivo models have to be performed to promote clinical application in patients. (C) 2007 Elsevier Inc. All rights reserved.