Chemosensitization of bladder cancer cell lines by human telomerase reverse transcriptase antisense treatment
Chemosensitization of bladder cancer cell lines by human telomerase reverse transcriptase antisense treatment
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DOI：
10.1097/01.ju.0000138157.46464.6e
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发表时间：
2004-11-01
影响因子：
6.6
通讯作者：
Meye, A
中科院分区：
文献类型：
--
作者：
Kraemer, K;Fuessel, S;Meye, A
目的：膀胱移行细胞癌(TCC)对丝裂霉素C(MMC)、顺铂、吉西他滨等常用化疗药物的疗效往往令人失望。由于人类端粒酶逆转录酶(HTERT)是一种肿瘤特异性表达基因，与大多数肿瘤的致死性和恶性程度有关，因此被认为是一种合适的抗肿瘤靶点。材料与方法：在4株TCC细胞株化疗前，用2hTERT反义寡核苷酸(AS-ODN)ASt2206和ASt2331对MMC、顺铂和吉西他滨的生长抑制作用进行了初步筛选。通过Annexin V染色和Western印迹分析检测活化的caspase-3来检测细胞的凋亡情况。无意义(NS)-ODN作为对照。结果：所有细胞株对所测试的抗癌药物都有反应。在大多数组合中，AS+CT处理对细胞活力的抑制作用明显强于NS+CT对照，表明AS具有特异性的增强作用。例如，在EJ28细胞中，ASt2331+MMC使存活率降低到17%，而NS+MMC(58%)则相反。与NS+CT相比，ASt2331+CT组的细胞凋亡率明显增加1.3~3.0倍。结论：hTERT反义寡核苷酸增强细胞毒药物对TCC细胞生长的作用，可减少化疗剂量，证实hTERT作为一种特定治疗方法的靶点是合适的。
Purpose: Responses of transitional cell carcinoma of the bladder (TCC) to commonly used chemotherapy agents such as mitomycin C (MMC), cisplatin and gemcitabine are often disappointing. Since human telomerase reverse transcriptase (hTERT) is tumor specifically expressed and contributes to the immortality and malignancy of the majority of tumors, it is regarded as a suitable antitumor target. We investigated whether combinations of hTERT antisense (AS)-oligonucleotides (ODNs) with common chemotherapy (CT) schedules may improve drug mediated antitumor effects.Materials and Methods: Initial screening for enhancement of the inhibitory effects of MMC, cisplatin and gemcitabine on viability by treatment with the 2 hTERT AS-ODNs ASt2206 and ASt2331 was performed in 4 TCC cell lines prior to CT. Apoptosis was assessed by annexin V staining and detection of activated caspase-3 using Western blot analysis. Nonsense (NS)-ODN served as a control in all experiments.Results: All cell lines responded to the anticancer agents tested. Treatment with AS plus CT resulted in a significantly stronger inhibition of viability than the NS plus CT control in the majority of combinations, indicating an AS specific enhancement effect. For example, ASt2331 plus MMC decreased viability to 17% in contrast to NS plus MMC (58%) in EJ28 cells. All ASt2331 plus CT combinations specifically increased the rate of apoptosis 1.3 to 3.0-fold compared with NS plus CT. Apoptosis induction was associated with caspase 3 activation.Conclusions: Enhancement of cytotoxic drug effects on the growth of TCC cells by hTERT AS-ODNs presented herein allows a dose decrease in chemotherapy and confirms the suitability of hTERT as a target in a specific therapy approach.